Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[S:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[CH:1]1([N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[S:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:20][CH2:21]3)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1ccc(OC2CCNCC2)cc1)N(c1cccc(F)c1)C1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)N1CCC(Oc2ccc(S(=O)(=O)N(c3cccc(F)c3)C3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{4-[cyclobutyl-(3-fluoro-phenyl)-sulfamoyl]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (330 mg, 655 μmol) in DCM (9 mL) was added TFA (1 mL) and then the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and then purified by SCX eluting with 2 M NH3 in MeOH to give N-cyclobutyl-N-(3-fluoro-phenyl)-4-(piperidin-4-yloxy)-benzenesulfonamide (195 mg, 483 μmol). To a solution of N-cyclobutyl-N-(3-fluoro-phenyl)-4-(piperidin-4-yloxy)-benzenesulfonamide in DCM (10 mL) was added DIPEA (168 μL, 965 μmol) and methanesulfonyl chloride (41 μL, 531 μmol) and the reaction was stirred at room temperature for 30 minutes. Water was added and then extracted with DCM, filtered through a phase separator and concentrated. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) followed by preparative reverse a phase HPLC gave the title compound (169 mg). 1H NMR δ (DMSO): 7.46 (2H, d, J=8.8 Hz), 7.38-7.39 (1H, m), 7.16-7.17 (3H, m), 6.77-6.78 (2H, m), 4.69-4.71 (1H, m), 4.20-4.22 (1H, m), 3.33-3.38 (4H, m), 3.13 (2H, ddd, J=12.1, 8.09, 3.4 Hz), 2.91 (3H, s), 2.03-2.06 (4H, m), 1.77-1.81 (4H, m), 1.53-1.56 (2H, m). LCMS (m/z, Method B) ES+ 482.9 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:15]=3)[S:11][C:7]=2[C:6]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:5][CH:4]=1.Cl.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(=O)(O)[O-].[Na+]>C1COCC1.O.C(N(CC)CC)C>[C:34]([N:30]1[CH2:31][CH2:32][CH:27]([C:6]2[C:7]3[S:11][C:10]([NH:12][C:13](=[O:26])[C:14]4[CH:19]=[CH:18][N:17]=[C:16]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[CH:15]=4)=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:28][CH2:29]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of 0.05 g (0.095 mMol) N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-2-morpholin-4-yl-isonicotinamide 1:2 hydrochloride in 3 ml THF were added 0.029 ml triethyl amine. At 0° C. 0.011 ml (0.11 mMol) acetic anhydride was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. This was extracted three times with 15 ml ethyl acetate, the combined organic phase were dried over sodium sulfate and evaporated to dryness in vacuo. One obtained 0.031 g (66%) N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-morpholin-4-yl-isonicotinamide as a white solid. F.p.: 231-233° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]#[C-:10])=[CH:5][CH:4]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]([CH3:44])[C:27]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([NH2:43])[N:38]=3)=[C:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=3)[C:22]=2[C:21]1=[O:45])=[O:19])([CH3:16])([CH3:15])[CH3:14].CC([O:50]C)(C)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]([CH3:44])[C:27]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([NH2:43])[N:38]=3)=[C:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=4)=[O:50])[CH:31]=3)[C:22]=2[C:21]1=[O:45])=[O:19])([CH3:15])([CH3:16])[CH3:14]
Reactant: [C-]#[N+]c1ccc(C(F)(F)F)cc1
Reactant: Cn1c2c(c(Cc3cccc(N)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Reactant: COC(C)(C)C
Solvent: ClCCl
Product: Cn1c2c(c(Cc3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
4-Trifluoromethyl-phenyl isocyanide (0.018 g, 0.096 mmol) was added to a solution of 3-(3-Amino-benzyl)-2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.039 g, 0.088 mmol) (prepared as described in Example 6) in DCM (2.0 ml) and the reaction mixture was stirred at room temperature for 3 h, under an argon atmosphere. MTBE (5.0 ml) was added to the reaction mixture and the organic layer was washed with purite water (1×5.0 ml), brine (1×5.0 ml), dried over Na2SO4. The filtrate was dried under vacuum and the crude was purified by reverse phase chromatography, affording 2-(2-Amino-pyrimidin-4-yl)-1-methyl-4-oxo-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-benzyl}-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.051 g, 0.080 mmol, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.[OH-:16].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][N:9]=2)[CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccnc(-c2cc(C=O)ccn2)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccnc(-c2cc(C(=O)O)ccn2)c1
Reaction time: 8 h
Yield: 77 %

Procedure:
A suspension of 4′-methyl-2,2′-bipyridine-4-carboxaldehyde (3.5 g, 15 mmol) in 95% EtOH (150 ml) was added a solution of AgNO3 (3.15 g) in water (32 ml). The suspension was stirred rapidly and 1M NaOH (79 ml) solution was added dropwise over 20 min to form Ag2O. The dark black solution was stirred for an additional 15 hrs. EtOH was removed by rotary evaporator and filtred to remove Ag2O and unreacted metallic Ag. The residue was washed with 1.3M NaOH (2*20 ml) and H2O 20 ml. The combined basic filterate was extracted with DCM to remove unreacted aldehyde and adjusted to pH 3.5 with 1:1(v/v) 4N HCl/AcOH to afford white compound. After keeping overnight at −10° C. the compound was collected and dried to afford pure compound 2.9 g (77%). Mass Spect. (FAB) MW 215 [M+]; NMR assigned.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccc(O)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Cl)ccc1Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of the product of Example 151A (400 mg, 1.506 mmol) and iron powder (336 mg, 6.02 mmol) in acetic acid (10 mL) and ethanol (10 mL) was heated at reflux under a nitrogen atmosphere for 25 minutes. The reaction was cooled to room temperature, diluted with water (50 mL), and treated with solid sodium carbonate until the pH was 6. Extracted with ethyl acetate (2×50 mL) and washed the organic with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Co-evaporating the resulting oil with methylene chloride/hexanes provided the title compound as a tan solid (355 mg, 100%).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@:3]1([CH2:16][F:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25].[OH-].[Na+]>O>[F:18][C:2]1([F:1])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@:3]1([CH2:16][F:17])[C:9]1[CH:14]=[C:13]([N+:24]([O-:26])=[O:25])[CH:12]=[CH:11][C:10]=1[F:15]
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@](CF)(c2ccccc2F)C(F)(F)CO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)C(F)(F)CO1
Reaction time: 2 h
Yield: 102.4 %

Procedure:
A dispersion of (S)-5,5-difluoro-4-fluoromethyl-4-(2-fluoro-phenyl)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate F6.1) (32.5 mg, 124 μmol) in sulfuric acid (1.01 g, 554 μl, 9.92 mmol) was cooled to 0° C. and stirring was continued until a complete solution was obtained. At 0° C. fuming nitric acid (12.1 mg, 8.68 μl, 174 μmol) was added in one portion and stifling continued for 2 hours. For the workup, the solution was added dropwise to a mixture of crushed ice and water. With an aqueous solution of sodium hydroxide (6 M) the pH was adjusted to 7-8. The aqueous layer was extracted three times with ethyl acetate, thereafter the combined organic layers were washed with brine, then dried over sodium sulphate and evaporated at reduced pressure. The (S)-5,5-difluoro-4-fluoromethyl-4-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (39 mg, quantitative yield) was obtained as a light yellow solid and was engaged in the following step without further purification. MS (ISP): m/z=308.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].C[C:10]1(C)[O:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]#[C:21][Si](C)(C)C)[C:13]=2[C:12](=[O:26])O1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=C(S(C)(=O)=O)[N:31]=1.P(=O)(O)(O)O>O.CN(C)C=O>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:10]([O:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]#[CH:21])[C:13]=2[C:12]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:26])[N:31]=1
Reactant: CC1(C)OC(=O)c2c(C#C[Si](C)(C)C)cccc2O1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: OCC(F)(F)F
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
2.0 g of 2,2,2-trifluoroethanol are introduced into 80 ml of dimethylformamide and 0.60 g of 80% strength sodium hydride is added at room temperature. After 1 h, a clear solution has formed and 5.0 g of 2,2-dimethyl-5-trimethylsilylethynyl-4H-(1,3)benzodioxin-4-one are added at room temperature. After 20 min, 4.0 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added and the reaction solution is stirred overnight at room temperature. It is then poured into 400 ml of water containing phosphoric acid (pH 3) at 0° C. and extracted with methyl tert-butyl ether, and the combined organic phases are washed with water, dried over sodium sulfate and concentrated. 6.4 g of crude product remain, which is chromatographed on silica gel using n-hexane/ethyl acetate. A colorless oil (1.2 g) is obtained. 1H-NMR (CDCl3): δ=3.33 (s); 3.83 (s); 4.55 (q); 5.80 (s); 7.25-7.50 (m).
Reaction SMILES: F[C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH:12]1([C:15]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20][C:19]=3[CH:18]=[C:17]3[O:33][CH2:34][CH2:35][N:36]([CH2:37][CH2:38][OH:39])[C:16]=23)[CH2:14][CH2:13]1.C[C:41](C)([O-:43])C.[K+].CO>C1COCC1.C(OCC)(=O)C>[C:4]([C:3]1[C:2]([O:43][CH3:41])=[CH:9][C:8]([O:39][CH2:38][CH2:37][N:36]2[C:16]3=[C:15]([CH:12]4[CH2:13][CH2:14]4)[C:25]4[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20][C:19]=4[CH:18]=[C:17]3[O:33][CH2:34][CH2:35]2)=[C:7]([F:11])[CH:6]=1)#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(c(C4CC4)c2CC1)N(CCO)CCO3
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCOc3cc4c(c(C5CC5)c32)CCN(C(=O)OC(C)(C)C)CC4)c(F)cc1C#N
Temperature: -30 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
To a solution of 210 mg of 2,4,5-trifluorobenzonitrile and 500 mg of t-butyl 5-cyclopropyl-4-(2-hydroxyethyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 15 ml of THF was added portionwise 150 mg of potassium t-butoxide, followed by stirring at −30° C. for 2 hours. Further, to the reaction mixture was added 0.15 ml of MeOH and then 150 mg of potassium t-butoxide was added portionwise thereto, followed by elevating the temperature to −10° C. and stirring for 15 hours. Further, to the reaction mixture were added 0.15 ml of MeOH, and then 150 mg of potassium t-butoxide was added portionwise thereto, followed by elevating the temperature to 0° C. and stirring for additional 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc)) to obtain 726 mg of t-butyl 4-[2-(4-cyano-2-fluoro-5-methoxyphenoxy)ethyl]-5-cyclopropyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a colorless viscous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([OH:18])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16](=[O:18])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 73.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 8-bromo-5-carboxy-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.96 mmol) and aniline (97 μL, 1.061 mmol) to give 274 mg of the title compound (74%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 (s, 1H), 10.45 (s, 1H), 7.59 (d, 2H, J=7.5 Hz), 7.34 (t, 2H, J=7.5 Hz), 7.23 (d, 1H, J=1 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.07 (d, 1H, J=1 Hz), 5.31 (dd, 1H, J=10, 5 Hz), 4.32 (d, 2H, J=5.6 Hz), 3.78 (dd, 1H, J=17, 10 Hz), 3.35 (dd, 1H, J=17, 5 Hz),
Reaction SMILES: [C:1]([C:3]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]3[N:18](C(OC(C)(C)C)=O)[CH:19]=[CH:20][N:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4]1)#N.[N:29]([C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1)=[C:30]=[S:31].Cl.C([O-])(O)=[O:46].[Na+]>CN(C=O)C.O.CO>[NH:21]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]2[C:30](=[S:31])[N:29]([C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:41])([F:43])[F:42])[CH:33]=3)[C:1](=[O:46])[C:3]32[CH2:6][CH2:5][CH2:4]3)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)n1ccnc1CCCc1ccc(NC2(C#N)CCC2)cc1
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCc4ncc[nH]4)cc3)C2=S)cc1C(F)(F)F
Temperature: 80 °C
Yield: 52 %

Procedure:
A mixture of tert-Butyl 2-(3-(4-(1-cyanocyclobutylamino)phenyl)propyl)-1H-imidazole-1-carboxylate (60) (22 mg, 0.06 mmol) and 4-isothiocyanato-2-trifluoromethylbenzonitrile (96) (26 mg, 0.12 mmol) in DMF (1 mL) was heated to 80° C. using microwave for 16 h. To this mixture was added methanol (3 mL) and aq. 1 N HCl (3 mL). The second mixture was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into cold water (30 mL), treated with saturated NaHCO3 solution and extracted with ethyl acetate (50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give 4-(5-(4-(3-(1H-Imidazol-2-yl)propyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (59) [ND-12] (29 mg, 52%) as a pale yellowish solid: 1H NMR δ 8.65 (br s, 1H), 7.97 (d, 1H, J=2.0 Hz) 7.96 (d, 1H, J=8.4 Hz) 7.84 (dd, 1H, J=8.4, 2.0 Hz), 7.34 (d, 2H, J=8.2 Hz) 7.19 (d, 2H, J=8.2 Hz) 3.00 (t, 2H, J=7.5 Hz) 2.73 (t, 2H, J=7.7 Hz), 2.47-2.77 (m, 4H), 2.13-2.25 (m, 3H), 1.51-1.71 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[F:18].[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[Si:23]([O:9][CH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[F:18])=[CH:4][CH:5]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2Cl)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2Cl)c1
Reaction time: 14 h
Yield: 252 %

Procedure:
To a solution of (6-chloro-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (3.00 g) and tert-butylchlorodiphenylsilane (1.53 g) in DMF (7.0 mL) was added imidazole (1.53 g) at room temperature, and the mixture was stirred for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7.10 g) as a pale-yellow crude oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:63])[C@H:60]([CH3:62])[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:63])[C@H:60]([CH3:62])[NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.4 g, 3.2 m mole), 1-hydroxybenzotriazol (476 mg, 3.5 m mole) and L-alanine benzylester p-toluene sulfonate (1.3 g, 3.5 m mole) were dissolved in DMF (5 ml), and WSC (0.64 ml) was added thereto while cooling to -15° C. The reaction was continued for 3 hours under cooling and then overnight at room temperature, and ethyl acetate (100 ml) was added thereto. The mixture was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and dried with anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure leaving an oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-alanine benzylester material.
Reaction SMILES: N[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[OH-:15].[Na+]>>[CH3:12][O:11][C:7]1[C:6]2[C:2](=[O:15])[NH:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: COc1cccc2c1C(N)=NS2(=O)=O
Agent: [Na+]
Product: COc1cccc2c1C(=O)NS2(=O)=O

Procedure:
2.5 gm (11.8 mmols) of 3-amino-4-methoxy-1,2-benzoisothiazole-1,1-dioxide were reacted with sodium hydroxide analogous to Example 4. The reaction mixture was acidified, whereby 4-methoxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide was obtained, which was subsequently heated at 200°-205° C. with 20 gm of pyridine hydrochloride. After cooling, the reaction mixture was extracted several times with boiling benzene, the residue was dissolved in water, and the aqueous solution was again extracted with boiling benzene. The combined benzene phases were dried and evaporated in vacuo. The residue was recrystallized from water, yielding 1.35 gm (57.5% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:5]=[C:4]([S:21][CH3:22])[N:3]=1.[NH2:23][NH2:24].O.[CH3:26]CO>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]3[N:3]([CH:26]=[N:23][N:24]=3)[C:4]([S:21][CH3:22])=[N:5][C:6]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCO
Reactant: CSc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1
Solvent: O
Product: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.28 g of 4-chloro-5-(4-fluoro phenyl)-2-methylthio-6-(4-pyridyl)pyrimidine (0.85 mmol) and 3 ml of NH2NH2—H2O in 20 ml EtOH in a 50-ml r.b.flask with a stir bar was stirred at 70° C. The solvents were evaporated and the residue was mixed with toluene. The residue was dried by removal water with toluene and further dried under vacuum at 50° C. overnight. The resulting light yellow solid was mixed with 40 ml of DCM, 4 ml of CH(OCH3)3, and 2 ml of TFA in a 100-ml r.b.flask with a stir bar. The reaction solution was stirred at RT overnight. The acidic reaction solution was neutralized to pH 8 with sat'd NaHCO3. The DCM layer was washed with brine (10 ml) and dried over Na2SO4. After removal of the DCM in vacuo, 8-(4-fluorophenyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine was obtained as yellow solid; MS m/z (M+H)+ 338.1; C17H12FN5S requir. 337.3.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].C(Cl)Cl>CO>[N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][N:9]([C:20](=[O:22])[CH3:21])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A 200 mL round bottom flask was charged with 125d (2.1 g, 12.9 mmol), triethylamine (5.5 mL, 38.7 mmol), acetyl chloride (1.1 mL, 15.5 mmol) and CH2Cl2 (100 mL). The mixture stirred at room temperature over night. After this time, the reaction mixture was concentrated under reduced pressure, and to the residue was added H2O (50 mL) and EtOAc (50 mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (100 mL). The combined aqueous extracts were back extracted with 9:1 CH2Cl2:MeOH (2×50 mL). The combined organics were dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2—9:1 CH2Cl2:MeOH to afford a 84% yield (2.3 g) of 125e.