Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([C:25](=O)[NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44]N[CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][N:26]4[CH2:44][CH2:45][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=5)[CH2:41][CH2:42]4)=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)cc3c21)NC(=O)OCc1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C[C@@H](Cn1ncc2ccc3oc(CN4CCN(c5ccccn5)CC4)cc3c21)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A solution of the product from Example 3, Step B (0.18 g, 0.475 mmol) in dichloromethane (20 mL) was cooled (ice bath) and thionyl chloride (0.052 mL, 0.71 mmol) added. The mixture was stirred for 30 min and then evaporated to a residue which was dissolved in dichloromethane (20 mL); this solution was evaporated and the residue dried under a vacuum. The residue was dissolved in dichloromethane (20 mL) and 1-(2-pyridyl)piperazine (0.5 mL, 3.4 mmol) was added, and the mixture was stirred at room temperature for one hour at which point additional 1-(2-pyridyl)piperazine (0.9 mL) was added. Solvent was removed by evaporation (45° C.) and THF (10 mL) was added, followed by heating the mixture at reflux temperature for one hour. This reaction mixture was evaporated and the residue dissolved in methanol (25 mL) and triethylamine (1.5 mL) followed by evaporation of this mixture to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate) to give a foamy solid (0.21 g, 84%): LC/MS m/z 525 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH3:12])[C:5]2=[N:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:11]([C:10]1[C:5]2[N:6]([C:2]([CH3:1])=[N:3][N:4]=2)[N:7]=[CH:8][CH:9]=1)[CH3:12]
Reactant: CCc1ccnn2c(C)nnc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnc2c(C(C)Br)ccnn12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of crude 3-methyl-8-ethyl-1,2,4-triazolo[4,3-b]pyridazine (0.6 g) was dissolved in anhydrous carbon tetrachloride (40 ml) and N-bromosuccinimide (0.66 g) with a catalytic amount of benzoylperoxide. The total mixture was stirred at room temperature for 45 minutes and then boiled under reflux for 2 hours. The solvent was eliminated at reduced pressure and water (100 ml) was added to the residual oil. The product was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate solution, then with water, dried with sodium sulphate, filtered and concentrated to dryness. The residual oil was purified by flash chromatography on silica gel using ethyl acetate as eluent to give 8-(1-bromoethyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine as a solid. Yield 0.41 g, m.p. 125-128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:23][C:24]1[CH:28]=[C:27]([CH2:29][C:30](O)=[O:31])[O:26][N:25]=1>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:30](=[O:31])[CH2:29][C:27]1[O:26][N:25]=[C:24]([CH3:23])[CH:28]=1
Reactant: Nc1ccccn1
Reactant: Cc1cc(CC(=O)O)on1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)Nc2ccccn2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General method for synthesis of N-pyridyl-3-methylisoxazoleacetamides: The desired aminopyridine (0.94 g, 10 mmol) was dissolved in 20 mL of THF at 0° C. and treated with DCC (2.06 g, 10 mmol), followed with a solution of 3-methyl-5-isoxazole acetic acid (1.41 g, 10 mmol) in 10 mL of THF. After stirring at rt overnight the solvent was removed in vacuo and the residue was purified by chromatography (10% MeOH/CH2Cl2), affording the desired N-pyridyl-3-methyl-5-isoxazoleacetamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:19]=1[O:20]C1C=CN=C2C=C(C3SC=CN=3)SC=12>>[F:17][C:18]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:19]=1[O:20][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Yield: 47 %

Procedure:
Starting from the chloride 175 and following the procedure described above for the synthesis of compound 11 (scheme 2, example 12), title compound 176 was obtained in 47% yield. LRMS (M+1) 371.0 (100%).
Reaction SMILES: Br[CH2:2][C:3]#[CH:4].[K].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>CN(C=O)C>[C:4]([N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11])#[C:3][CH3:2]
Reactant: C#CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC#CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C

Procedure:
32.3 g (271 mmol) 3-bromopropine are dissolved in 150 ml DMF and 50.3 g (271 mmol) phthalimide potassium salt are added under ice cooling. The suspension is warmed at 70° C. for eight hours. The mixture is concentrated under a vacuum and the residue is distributed between acetic acid ethyl ester and water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized from acetic acid ethyl ester: Yield 36.4 g (72%) colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[OH:3].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:2]([CH3:1])[O:3][C:25]2=[O:27])[CH2:16][CH2:15]1)([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1OC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol from Step 2 above (1.9 g, 5.9 mmol) was stirred in dry THF in an ice bath under nitrogen, and triphosgene (0.59 g, 1.98 mmol) was added followed by triethylamine (2.5 ml, 1.8 g, 17.8 mmol). The ice bath was removed and the mixture was stirred at ambient temperature for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with 1N HCl followed by saturated sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 1-(1-Boc-4-piperidyl)-4-methyl-3,1-benzoxazin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:12]\[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)/[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:9]([Cl:21])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C(=C/c1ccco1)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(=Cc1ccco1)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A suspension of (E)-2-(4-bromophenyl)-3-furan-2-ylacrylic acid (Preparation 9, 4.10 g, 14.0 mmol) and oxalyl chloride (2.5 mL, 28.0 mmol) in anhydrous CH2Cl2 (100 mL) was treated with a catalytic amount of anhydrous DMF (25 μL). The resulting solution was stirred at 20° C. for 4 h, then the solvents were removed under reduced pressure. CH2Cl2 (50 mL) was added to the residue, then the solvents were evaporated off under reduced pressure to give 2-(4-bromophenyl)-3-furan-2-ylacryloyl chloride as a brown solid. A solution of this acid chloride (343 mg, 1.1 mmol) in anhydrous THF (1 mL) was added to a solution of 5-chlorothiazol-2-ylamine hydrochloride (171 mg, 1.0 mmol) and NEt3 (0.56 mL, 4.0 mmol) in anhydrous THF (1 mL). The suspension was stirred for 16 h at 20° C., then the solvents were removed under reduced pressure. The residue was partitioned between CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was washed with H2O (5 mL) and brine (5 mL), before being concentrated. The resulting solid was recrystallised from MeOH to furnish the title compound: RTA=4.39 min; m/z (ES+)=410.9 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([O:28][CH2:29][CH3:30])[CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:31]([O:33][CH3:34])=[O:32])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH2:29]([O:28][C:21]1[CH:20]=[C:19]([C:17]2[CH:16]=[CH:15][C:14]3[NH:8][CH2:9][CH2:10][C:11]([C:31]([O:33][CH3:34])=[O:32])=[CH:12][C:13]=3[CH:18]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][CH3:27])[CH3:30]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1OCC
Temperature: 80 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
In ethyl acetate (50 ml) was dissolved methyl 1-(t-butoxycarbonyl)-7-(3,4-diethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.3 g). To the solution was added 6N hydrochloric acid (10 ml), and the mixture was stirred at 80° C. for 1 hour, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-(3,4-diethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.7 g) as yellow crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[C:18]([C:23]([O:25]CC)=[O:24])=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].[OH-].[Na+]>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([C:23]([OH:25])=[O:24])=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:28][CH:29]=1)=[O:11]
Reactant: CCOC(=O)c1nccnc1Oc1ccc(C(=O)c2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(Oc2nccnc2C(=O)O)cc1)c1nc2ccccc2[nH]1

Procedure:
To the solution of ethyl 3-(4-(1H-benzo[d]imidazole-2 carbonyl)phenoxy)pyrazine-2-carboxylate (30 g, 77 mmol) in methanol (250 mL) was added aqueous NaOH solution (4.62 g, 115 mmol) in 50 mL of water. The reaction mixture was heated to reflux for 1 h. The reaction mixture was concentrated then diluted with water. The aqueous layer was washed with ethyl acetate and then acidified by addition of 2N HCl to pH 6. The precipitate was collected by filtration, dried to give the title compound as a light brown solid. MS [M+H]=351.2.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH2:27].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(O)(=O)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH:27][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1n[nH]c(CN)c1Oc1cc(Cl)cc(Cl)c1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1n[nH]c(CNCc2ccc(F)cc2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 3 h
Yield: 19.7 %

Procedure:
Sodium triacetoxyborohydride (36 mg, 0.160 mmol) was added in one portion to a stirred solution of the pyrazole of Example 109 (150 mg, 0.400 mmol), 4-fluorobenzaldehyde (11 mg, 0.080 mmol) and acetic acid (3 drops) in dichloromethane (15 ml) at room temperature under nitrogen. The reaction was stirred for 3 hours and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (90:9:1, by volume) to provide the title compound (6 mg) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:39])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:39])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[CH:20][C:21]=1[C:22]([F:24])([F:25])[F:23])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-({5-[(2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.10 g, 0.17 mmol) in DCM (5 mL) was added TFA (1.5 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.14 g of crude product which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:26])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:27]>Cl>[ClH:27].[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:26])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:27]
Reactant: COc1nc(N)c(Cl)cc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: COc1nc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
A mixture of tert-butyl 4-{3-[6-amino-5-chloro-2-(methyloxy)-3-pyridinyl]-3-oxopropyl}-1-piperidinecarboxylate (step 5, 610 mg, 1.53 mmol) in 10% methanolic hydrochloric acid (6 ml) was stirred at room temperature for 18 h. The formed solid was collected by filtration, washed with methanol and dried to give 242.0 mg (47%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([N:8]([CH2:10][C:11](O)=[O:12])[CH3:9])[CH:7]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+].CCOC(C)=O>C(O)C.O.Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][C:11](=[O:12])[CH2:10][N:8]2[CH3:9]
Reactant: CN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CC(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Yield: 36.1 %

Procedure:
A solution of [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid (8 g, 27.6 mmol) and tin(II) chloride dihydrate (20 g, 88 mmol) in ethanol (200 Ml), water (30 ml) and concentrated HCl (10 ml) was heated to reflux for 6 hours. After cooling to room temperature the mixture was diluted with water and was adjusted to pH 9 with 2N aqueous sodium hydroxide solution. After addition of EtOAc, the precipitated tin hydroxide was filtered off. The layers were separated and the organic layer was washed with water, then brine, dried (MgSO4) and evaporated. The residue was recrystallized from ethanol to afford 6-bromo-4-methyl-3,4-dihydro-1H-quinoxalin-2-one (2.4 g, 36%), which was used without further purification. 1H-NMR (DMSO-d6) δ 2.78 (s, 3H), 3.89 (s, 2H), 6.81 (d, 1H, J=1.76 Hz), 6.95 (dd, 1H, J=8.49, 1.81 Hz), 7.05 (d, 1H, J=8.47 Hz), 10.63 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.O>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:36]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:35]=1[O:34][CH3:33])[C:8](=[O:11])[O:9][CH3:10]
Reactant: COc1ccc(C)cc1B(O)O
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C)ccc1OC

Procedure:
A mixture of methyl [3,5-bis(trifluoromethyl)benzyl][2-iodo-5-(trifluoromethyl)benzyl]carbamate (0.10 g, 0.17 mmol) from Example 5, and 2-methoxy-5-methylphenyl boronic acid (0.034 g, 0.2 mmol), palladium acetate (0.0038 g, 0.017 mmol) and potassium carbonate (0.047 g, 0.34 mmol) in 4:1 acetone/water (10 ml) was heated and maintained at reflux for 1 h. The color of the solution turned dark. Acetone was removed and the residue was extracted with methylene chloride (3×10 ml). The combined organic layers were washed with water, then brine, and dried over sodium sulfate. The title compound was obtained as a colorless oil by preparative thin layer chromatography using acetone/hexane (5:95) as the eluant. 1H NMR (CDCl3, 500 MHz): δ 7.73 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.47 (s, 2H), 7.35 (m, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.19 (m, 1H), 6.85 (m, 2H), 4.23-4.36 (m, 4H), 3.79 (m, 3H), 3.68 (s, 3H), 2.25 (s, 3H). LC-MS (M+1): 580.0 (4.61 min).
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]#[N:19])[C:15]([OH:20])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:32][NH2:33])=O)=[CH:25][CH:24]=1>>[O:21]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]2[NH:19][C:30]([CH2:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[N:32][N:33]=2)[C:15]([OH:20])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: N#Cc1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Product: O=S1(=O)CCCCN1c1nc(-c2nnc(Cc3ccc(F)cc3)[nH]2)c(O)c2ncccc12

Procedure:
The title compound was prepared in a similar manner to that described in example 3 from 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carbonitrile (12 mg, 0.04 mmol) and 2-(4-fluorophenyl)acetic hydrazide (33 mg, 0.20 mmol) to give a white solid (6 mg, 31%). 1H NMR (CDCl3/CD3OD): δ 9.13 (m, 1 H), 8.56 (d, J=8.4 Hz, 1 H), 7.63 (dd, J=8.4, 4.0 Hz, 1 H), 7.32 (dd, J=8.4, 5.6 Hz, 2 H), 6.99 (t, J=8.4 Hz, 2 H), 4.17 (s, 2 H), 3.90 (m, 1 H), 3.77 (m, 1 H), 3.52 (m, 1 H), 3.32 (m, 1 H), 2.44-1.89 (m, 4 H); 19F NMR (CDCl3/CD3OD): δ −116.86; MS m/z 455 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:13](=O)[CH3:14])[C:8](OCC)=[O:9])=[C:4]([O:18][CH3:19])[CH:3]=1.C(=O)(O)O.[NH2:24][C:25]([NH2:27])=[NH:26]>CCO>[NH2:27][C:25]1[N:26]=[C:8]([OH:9])[C:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([OH:1])=[CH:3][C:4]=2[O:18][CH3:19])=[C:13]([CH3:14])[N:24]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OC)C(C)=O
Agent: O=C(O)O
Solvent: CCO
Product: COc1cc(O)ccc1Cc1c(C)nc(N)nc1O

Procedure:
A mixture of the product from step (ii) (23.35 g) and guanidine carbonate (15.9 g) in EtOH (300 ml) was heated under reflux for 24 h. The mixture was cooled and the solid filtered and washed with EtOH, water, EtOH then diethyl ether and dried to afford the subtitle compound, 11.36 g.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C@@H:11]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O>CN(C)C=O>[N:1]([CH2:10][C@@H:11]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
36 mg (0.55 mmol) of sodium azide are added to a solution of 218 mg (0.55 mmol) of (2S)-2,5-bis[(tert-butoxycarbonyl)amino]pentyl methanesulfonate (Example Z7) in 15 ml of dimethylformamide and the mixture is stirred at 70° C. for 12 h. Most of the solvent is distilled off in vacuo, and the residue is diluted with ethyl acetate. The solution is washed several times with a saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([O:18]C)=[C:13]([CH3:20])[CH:12]=3)[O:8][C:6]=2[N:7]=1.B(Br)(Br)Br.[Na]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH3:20])[C:14]([OH:18])=[C:15]([CH3:17])[CH:16]=3)[O:8][C:6]=2[N:7]=1
Reactant: COc1c(C)cc(-c2nc3cnc(Cl)nc3o2)cc1C
Agent: BrB(Br)Br
Agent: [Na]
Solvent: ClCCl
Product: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 1.2 g of 5-chloro-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine in 42 ml of dichloromethane was cooled to 0° C., and over a period of 10 min 10 ml of a 1 M solution of boron tribromide in dichloromethane was added. The mixture was stirred at 0° C. for 1 h, and then another 3 ml of a 1 M solution of boron tribromide in dichloromethane were added. After stirring for another 1 h, 20 ml of a saturated aqueous solution of sodium hydrogencarboante were added slowly. The precipitate was filtered off and washed with water to give 1 g of the title compound.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)[C:22]([CH3:38])=[CH:21][N:20]=1>N1C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=5)[C:22]([CH3:38])=[CH:21][N:20]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(N)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 90 °C

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (91 mg, 0.35 mmol) and tert-butyl 4-(2-amino-5-methylpyrimidin-4-yl)benzoate (50 mg, 0.175 mmol), pyridine (2 mL) was added. The reaction was heated at 90° C. for twenty four hours. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in EtOAc and filtered. The filtrate was washed with saturated aqueous NaHCO3 (×3). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 4-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoate. ESI-MS m/z calc. 509.2. Found 510.5 (M+1)+. Retention time 2.18 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:13].O>CS(C)=O>[NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(N)c1C
Reactant: Br
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(Br)cc(C(=O)O)c(N)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-3,4-dimethylbenzoic acid (50.0 g) in DMSO (500 mL) was added hydrobromic acid (174 mL) while keeping the internal temperature at 25 to 30° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water (500 mL), and the mixture was stirred for 30 min. The precipitate was collected by filtration, and washed with water to give the title compound (102 g: containing DMSO).