Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:28])[CH2:13]2)=[O:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:31]([O:35][C:36]([N:38]([CH:51]([CH3:53])[CH3:52])[CH2:39][CH:40]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].ClCCl.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:27][CH2:26][CH2:25][N:24]([C:41](=[O:42])[C@@H:40]([C:44]5[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=5)[CH2:39][N:38]([C:36]([O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:37])[CH:51]([CH3:52])[CH3:53])[CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:28])[CH2:13]2)=[O:10])=[CH:29][CH:30]=1)([O-:4])=[O:3]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCCNCC3)c21
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCCN(c2ncnc3c2[C@H](C)C[C@H]3OC(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Yield: 49.5 %

Procedure:
(5R,7R)-4-(1,4-Diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate hydrochloride (61 mg, 0.140 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (48 mg, 0.140 mmol) were suspended in dichloromethane (5 mL) N,N-Diisopropylethylamine (54 mg, 0.420 mmol) was then added. HBTU (53 mg, 0.140 mmol) was added, and the resultant solution was stirred at ambient for 16 hours. After this time, the reaction mixture was quenched by the addition of saturated sodium carbonate solution and then extracted twice with dichloromethane. The combined organic portions were dried over sodium sulfate, filtered, and concentrated. The residue thus obtained was purified by silica gel chromatography to give (5R,7R)-4-(4-((S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoyl)-1,4-diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (50 mg, 50%). LCMS (APCI+) M+=721.1, Rt=4.51 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([Cl:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:28]3[CH:27]=[C:26]([Cl:25])[CH:31]=[C:30]([Cl:32])[CH:29]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3cc(Cl)cc(Cl)c3)ccc2F)c1

Procedure:
The phenyl bromide (139) (50 mg, 0.13 mmol) was coupled to 3,5-dichloro-phenylboronic acid (24 mg, 0.13 mmol) using method E. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:6](Cl)=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1>C(OCC)C>[NH2:1][C:3]1[N:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: N
Reactant: Fc1nc(OC(F)(F)F)c(Cl)c(C(F)(F)F)n1
Solvent: CCOCC
Product: Nc1nc(OC(F)(F)F)cc(C(F)(F)F)n1
Reaction time: 2 h

Procedure:
4.7 g (0.278 mol) of gaseous ammonia were passed over the course of 1 hour into a stirred mixture of 38.0 g (0.147 mol) of 2-fluoro(chloro)-4-trifluoromethoxy-6-trifluoromethylpyrimidine and 150 ml of diethyl ether at -75° to -70° C. The mixture was stirred for 2 hours each at -75° and at 25° C. The precipitate was filtered off with suction, and the organic phase was extracted with water, dried and evaporated. Chromatography on silica gel with methyl tert.-butyl ether yielded 20.4 g (56.1% of theory) of the title compound of melting point 47°-49° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:21][N:22]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNCCc1ccccc1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(N(C)CCc3ccccc3)c2)c1
Temperature: 200 °C
Yield: 67 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.5 g, 0.0018 mol) and N-methylphenethylamine (15 mL) was heated at 200° C. for 24 hours. The excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.45 g (67% yield) of product as a yellow oil: Anal. Calc'd. for C25H26N4: C, 78.50; H, 6.85; N, 14.65. Found: C, 78.43; H, 6.87; N, 14.30.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[N:27]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: COc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.18 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 9 mg (0.21 mmol) of 60% sodium hydride, 44 mg (0.22 mmol) 2-bromomethyl-6-methoxy-pyridine and 0.8 mL of N,N-dimethylformamide. Yield: 45 mg of a white solid: LC-MSD, m/z for C25H22N2O3 [M+H]+=399.3; HPLC retention time: 2.8 min.
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:32])[CH:15]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])C1C=CC=CC=1.[OH:33]O.[Li+].[OH-]>C1COCC1.O>[CH:26]1([CH2:25][CH:15]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[O:18])[C:14]([OH:32])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C(CC(CC1CCCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1)N1CCOCC1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1

Procedure:
A 0.05 M solution of 1-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-butane-1,4-dione (1 g) in 3:1 −THF/H2O was treated at 0° C. with 8 equivalents of 30% H2O2 followed by 2.0 equivalents of LiOH. The resulting mixture was stirred at 0–25° C. until the substrate had been consumed (approximately 1 hour). The excess peroxide was quenched at 0° C. with a 10% excess of 1.5 N aqueous Na2SO3. After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by MeCl2 extraction. The carboxylic acid was isolated by EtOAc extraction of the acidified (pH 1–2) aqueous phase, then recrystallized from EtOAc and hexane to yield 0.58 g of 2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]1[C:14]([CH3:17])=[CH:15][S:16][C:7]1=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH3:22][NH:23][CH:24]1[CH:32]=[CH:31][CH2:30][CH:29]2[CH:25]1[CH2:26][NH:27][CH2:28]2>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:27]1[CH2:26][CH:25]3[CH:29]([CH2:30][CH:31]=[CH:32][CH:24]3[NH:23][CH3:22])[CH2:28]1)[N:8]1[C:14]([CH3:17])=[CH:15][S:16][C:7]1=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: CNC1C=CCC2CNCC21
Reactant: Cc1csc2c(C(=O)O)c(=O)c3cc(F)c(F)c(F)c3n12
Solvent: CS(C)=O
Product: CNC1C=CCC2CN(c3c(F)cc4c(=O)c(C(=O)O)c5scc(C)n5c4c3F)CC21

Procedure:
100 mg (0.318 mmol) of 7,8,9-trifluoro-1-methyl-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid are heated at 80° C. under argon for 2 hours with 97 mg (0.64 mmol) of 2-methylamino-8-azabicyclo[4.3.0]-non-3-ene in 3 ml of DMSO. The mixture is concentrated in a high vacuum, the residue is recrystallized from ethanol and the product is dried.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38]1([CH2:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Na]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:45](=[O:46])[CH2:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Na]
Product: CC(C)(Cc1c(C(=O)Cc2ccccc2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy) indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using phenylacetyl chloride in place of trimethylacetyl chloride in Step B. Anal. C, H, N for sodium salt·1H2O Calc. C 69.46; H 5.22; N 4.26 Found C 69.71; H 5.25; N 4.11.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:5]([NH2:13])[NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:20](OC)(=[O:23])[C:21]#[CH:22]>CCO>[NH2:13][C:5]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:2]2[NH:1][C:20](=[O:23])[CH:21]=[CH:22][N:3]2[N:4]=1
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Reactant: C#CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C=CCOC(=O)c1c(N)nn2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (1.0 g, 5.4 mmol) and Cs2CO3 (2.5 g, 7.6 mmol) in EtOH (10 mL) was added methyl prop-2-ynoate (553.0 mg, 586.0 μl, 6.5 mmol), dropwise over 15 minutes and the reaction mixture was stirred overnight at room temperature. The deep orange mixture was filtered. The filtrate was cooled on an ice-bath and ether (100 mL) was slowly added with stirring. The mixture was stirred at 0° C. for 20 minutes by which time a yellow solid had precipitated out of solution. The solid was filtered, further triturated in ether (20 mL) and filtered. The yellow solid was dried to afford allyl 2-amino-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (700 mg, 54% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1.C(=O)([O-])[O-:13].[Ca+2]>O1CCOCC1.O>[OH:13][CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccc2nsnc2c1
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc2nsnc2c1
Yield: 76.4 %

Procedure:
5-Bromomethylbenzo-2,1,3-thiadiazole (4.8 g) and calcium carbonate (10 g) were heated at reflux in 1:1 dioxane/water (120 mL) for 3 hours. The solvents were evaporated and the residue was partitioned between 2N hydrochloric acid and methylene 6 3 chloride. The organic layers were dried (magnesium sulfate), evaporated and chromatographed on silica gel eluting with 1:1 ethyl acetate/hexane to provide 2.66 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(C(O)=O)[C:25]([OH:27])=[O:26])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1>C(O)(=O)C>[CH3:1][C:2]1[N:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]([OH:27])=[O:26])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCC(C(=O)O)(C(=O)O)c1ccccc1
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCC(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
(Scheme 4 (T)) A solution of starting material 2-[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-2-phenyl-malonic acid (580 mg, 1.32 mmole)) in glacial Acetic Acid (20 ml) was let stirred under reflux for 18 hrs. The next day, the reaction was let cooled to room temperature and concentrated in vacuo. Product was obtained 398.6 mg, 77.7%). 1H NMR (CDCl3): δ1.11 (b, 4H), 1.42 (bd, 2H), 1.59 (m, 1H), 1.96 (m, 1H), 2.55 (s, 3H), 3.43 (t, 1H), 3.96 (t, 2H), 7.199 (m, 3H), 7.27 (m, 7H), 7.39 (m, 2H), 7.45 (m, 3H), 11.857 (b, 1H), 13C NMR (CDCl3): δ6 12.0, 21.4, 26.1, 26.8, 29.5, 29.7, 33.1, 44.2, 52.2, 127.0, 127.2, 127.4, 128.0, 128.4, 128.4, 128.5, 129.1, 129.3, 129.5, 130.6, 131.0, 133.0, 139.8, 144.1, 175.8, 177.7. Mass Spec: 439.24 (MH+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][O:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[NH2:17])=[O:11]>C(O)=O>[CH3:8][O:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[NH:17][CH:1]=[O:3])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1sccc1N
Solvent: O=CO
Product: COC(=O)c1sccc1NC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Formic acid (40 mL) was added to acetic anhydride (60 mL) while cooling in an ice bath. Solid 3-amino-2-thiophenecarboxylic acid methyl ester (77, 10.3 g, 66 mmol) was added to the cold solution in small portions. The cooling bath was removed and the resulting suspension was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (100 mL) and the solid product collected by vacuum filtration to yield 3-(formylamino)-2-thiophenecarboxylic acid methyl ester (10.3 g, 85% yield) as a white solid.
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[C:25]([CH3:26])=[N:24][N:23]=[N:22]2)=[C:18](N)[CH:19]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:21]2[C:25]([CH3:26])=[N:24][N:23]=[N:22]2)=[C:16]([S:11][CH3:12])[CH:15]=1
Reactant: CSSC
Reactant: Cc1nnnn1-c1ccc(Br)cc1N
Agent: CC(C)CCON=O
Product: CSc1cc(Br)ccc1-n1nnnc1C
Temperature: 85 °C
Yield: 140.3 %

Procedure:
A solution of isoamyl nitrite (402 μL, 3 mmol) in dimethyl disulfide (2 mL, 22 mmol) at 25° C. was slowly treated with 5-bromo-2-(5-methyl-tetrazol-1-yl)-phenylamine (0.51 g, 2 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (50 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 6/1 to 5/1 hexanes/ethyl acetate) afforded 1-(4-bromo-2-methylsulfanyl-phenyl)-5-methyl-1H-tetrazole (0.8 g) as a brown solid that was used without further purification and characterization.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][O:11][C:12]1[N:16]([C:17]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][CH:13]=1.[C:26](#N)C.O>>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][O:11][C:12]1[N:16]([C:17]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][CH:13]=1
Reactant: CC#N
Reactant: Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)c(F)c1F
Solvent: O
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)c(F)c2F)c1

Procedure:
The title compound was prepared from 2-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 94) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 2.31 (3H, s), 3.96 (3H, s), 5.27 (2H, s), 5.80 (1H, d, J=6.4 Hz), 6.94-6.97 (1H, m), 7.13-7.17 (1H, m), 7.58 (1H, s), 7.76 (1H, d, J=4.0 Hz), 8.30 (1H, s), 8.69 (1H, d, J=2.4 Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=3.485 min. [M+H] Calc'd for C18H15F2N3O3, 360; Found, 360.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:38][O:39][C:40]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]2[C:41]=1[C:42](=[O:64])[NH:43][C:44]([C:52]1[CH:57]=[CH:56][C:55]([N:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=1)=[N:45]2>C1COCC1>[CH3:38][O:39][C:40]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]2[C:41]=1[C:42](=[O:64])[NH:43][C:44]([C:52]1[CH:57]=[CH:56][C:55]([N:58]3[CH2:59][CH2:60][N:61]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:8])[CH2:62][CH2:63]3)=[CH:54][CH:53]=1)=[N:45]2
Reactant: O=C(O)c1cccs1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cccs5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.9 %

Procedure:
To a solution of 2-thiophenecarboxylic acid (0.087 g, 0.68 mmol) in THF (20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCl (0.141 g, 0.74 mmol), Et3N (0.10 mL, 0.74 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.250 g, 0.68 mmol). The resulting solution was stirred at room temperature for 4 hours. The solution was concentrated in vacuo. The material was purified by flash chromatography, eluting with 0% to 50% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.100 g, 30%). 1H NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.75-7.84 (m, 1H), 7.46-7.53 (m, 1H), 7.12-7.20 (m, 1H), 7.03 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.74-3.92 (m, 4H), 3.37-3.49 (m, 4H). APCI MS m/z 477 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7]O)=[C:5]([CH3:9])[O:4][N:3]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:9]
Reactant: BrP(Br)Br
Reactant: Cc1noc(C)c1CO
Solvent: ClCCl
Product: Cc1noc(C)c1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3,5-dimethyl-1,2-oxazol-4-yl)methanol (805 mg, 6.3 mmol) in anhydrous dichloromethane (60 mL) was added dropwise phosphorus tribromide (1.2 mL, 12.6 mmol). The mixture was stirred at room temperature for 3 hours. Dichloromethane was evaporated, and the residue was dried in vacuo, affording 4-(bromomethyl)-3,5-dimethyl-1,2-oxazole. The product was used without further purification.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]>C(O)C>[N:12]([C:15](=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH3:2])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1ccccc1C=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccccc1OC)N=[N+]=[N-]
Temperature: -18 °C
Reaction time: 3 h

Procedure:
Pieces of sodium (3.678 g, 160 mmol) were added portionwise to ethanol (200 ml) over a period of 30 minutes. The resulting solution was cooled to −18° C. and a mixture of 2-methoxybenzaldehyde (4.832 g, 40 mmol) and ethyl azidoacetate (160 mmol) were then added over a period of one hour at a rate which allowed the temperature to be maintained below −15° C. After 3 hours, the solution was stored at 5° C. for 2 days in order to give a crystalline product which was collected by filtration and washed with cold hexane.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[S:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[OH:19])(=[O:10])=[O:9].[CH:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[O:48])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1>CN(C=O)C>[C:40]1([C:37]2[CH:36]=[CH:35][CH:34]=[CH:39][CH:38]=2)[CH:41]=[CH:42][C:43]([NH:46][C:47](=[O:48])[NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=2)[CH2:6][N:7]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[S:8]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[OH:19])(=[O:9])=[O:10])=[CH:44][CH:45]=1
Reactant: NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
To a solution of N-(3-(aminomethyl)benzyl)-3,5-dichloro-2-hydroxy-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide (60 mg, 0.12 mmol) in DMF (3 mL) was added 4-biphenyl isocyanate (23.7 mg, 0.12 mmol). The resulting mixture was stirred at rt. for 2 h under nitrogen. The mixture was concentrated and dissolved in MeOH, purified by preparative HPLC. The fractions containing the desired product were combined, concentrated and lyophilized to give white solid (50 mg, 60%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][SH:23])[CH3:16].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][S:23][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:16]
Reactant: Ic1ccc2c(ccc3nccn32)c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nccn32)c1
Temperature: 80 °C

Procedure:
1g (120 mg, 0.5 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (110 mg, 0.5 mmol) were dissolved in 1,4-dioxane (5 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.15 mL, 0.84 mmol), Pd2dba3 (10 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 80° C. overnight, then cooled to room temperature, concentrated, and purified by silica gel chromatography to give the desired product, 1i.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([F:17])[N:3]=1.[C@H:18]1([NH2:25])[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1>C(O)C>[F:17][C:4]1[N:3]=[C:2]([NH:24][C@H:21]2[CH2:22][CH2:23][C@H:18]([NH2:25])[CH2:19][CH2:20]2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: Fc1cc(-c2c[nH]c3ncccc23)cc(F)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2cc(-c3c[nH]c4ncccc34)cc(F)n2)CC1

Procedure:
A mixture of EXAMPLE 56B (0.60 g, 2.60 mmol) and trans-cyclohexane-1,4-diamine (1.04 g, 9.08 mmol) in ethanol (10 mL) was heated at in a Biotage Initiator microwave reactor at 170° C. for 80 minutes. After concentration, the residue was treated with 20% brine and extracted twice with ethyl acetate. The combined organic layers were concentrated and purified on a 110 g silica column (KP-NH from Biotage) eluting with ethyl acetate/methanol (97:3 to 90:10) to give the title compound.