Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]4[N:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=4)[CH:12]=3)[CH2:7]2)[C:5](=[O:25])[NH:4][C:3]1=[O:26].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:27]1([C:22]([C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[CH2:7][C:6]3([C:5](=[O:25])[NH:4][C:3](=[O:26])[N:2]3[CH3:1])[CH2:14]4)[CH:17]=2)=[O:24])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(Nc3cc(C(=O)O)ncn3)cc1C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C12Cc1ccc(Nc3cc(C(=O)N4CCc5ccccc54)ncn3)cc1C2

Procedure:
80.0 mg (0.23 mmol) 6-(3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidin-4,2′-inden]-5′-ylamino)pyrimidine-4-carboxylic acid, 30 μL (0.27 mmol) 2,3-dihydro-1H-indole, 70 μL (0.50 mmol) triethylamine and 80.0 mg (0.25 mmol) TBTU in 1.5 mL DMF were stirred for 4 h at RT. The reaction mixture was filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined, concentrated by rotary evaporation and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Br)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 611.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(OCCO)C>[CH3:12][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: C1CNCCN1
Solvent: CCOCCO
Product: Cc1cc(N2CCNCC2)c2ccccc2n1
Temperature: 140 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
4-Chloro-2-methylquinoline (1.8 g, 10 mmol) and anhydrous piperazine (5.25 g, 60 mmol) were dissolved in ethyleneglycol monoethylether (15 ml) and stirred at 140° C. overnight. The mixture was concentrated under reduced pressure, toluene was added (2×100 ml) and the solvent removed under reduced pressure. To the residue was added 0.5 M NaOH (100 ml) and the mixture was extracted with a mixture of dichloromethane/diethylether/ethyl acetate (1:1:1, 3×100 ml). The combined organic phases were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. 2.78 g of an off-white solid (8.5 mmol, 85%) were obtained that were used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>O>[C:17]([NH:21][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1
Solvent: O
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(4-fluoro-phenylethynyl)-pyrimidine (1 equiv.) in tert-butylamine (0.2 M) is heated at 80° C. in a sealed tube for 24 h. The mixture is cooled to rt, diluted with water, and extracted with EtOAc. The organic layer is concentrated and the residue purified by column chromatography to provide the title compound.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]3[CH2:21][CH:20](O)[CH2:19]3)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.C(N(S(F)(F)[F:30])CC)C>ClCCl>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]([F:30])[CH2:19][CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1CC(c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)C1
Solvent: ClCCl
Product: C=CCC(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Yield: 32.3 %

Procedure:
3-[3-(4-Difluoromethoxy-phenylethynyl)-phenyl]-cyclobutanol (0.820 gm, 2.61 mmol) was dissolved in dichloromethane (10 ml) and treated with (diethylamino)sulfur trifluoride (DAST, 0.500 gm, 3.20 mmol). Upon completion of reaction as determined by thin layer chromatography (TLC) the crude material was absorbed onto silica and purified by column chromatography (gradient elution; 0%-10% EtOAc in hexanes) to yield an oil 267 mg (32%); 1H NMR (500 MHz, DMSO-d6) δ ppm 2.55-2.75 (m, 2H) 4.97-5.20 (m, 2H) 5.52-5.83 (m, 2H) 7.04-7.32 (m, 3H) 7.40-7.48 (m, 2H) 7.50-7.55 (m, 2H) 7.62 (d, J=8.8 Hz, 2H); MS (EI) m/z 316 [M+·].
Reaction SMILES: C([NH:4][C:5]1[C:23]([Cl:24])=[CH:22][C:8]([C:9]([NH:11][CH:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[O:10])=[C:7]([O:25][CH3:26])[CH:6]=1)(=O)C.[OH-].[K+].CCOCC>C(O)C.O>[NH2:4][C:5]1[C:23]([Cl:24])=[CH:22][C:8]([C:9]([NH:11][CH:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[O:10])=[C:7]([O:25][CH3:26])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CCN2CCCCC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN2CCCCC2C1
Yield: 75 %

Procedure:
Hydrolysis of 4-acetylamino-5-chloro-2-methoxy-N-(2-quinolizidinyl)-benzamide (600 mg) with potassium hydroxide (500 mg) in ethanol (10 ml) and water (2 ml) at reflux for 4 hours followed by isolation through ether afforded one of the isomers of 4-amino-5-chloro-2-methoxy-N-(2-quinolizidinyl)-benzamide (400 mg), m.p. 175°-8°.
Reaction SMILES: C(OC(=O)[N:7]([CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:8])(C)(C)C.Cl[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([CH:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[CH:15][CH:16]=2)[CH2:9][NH:7][CH3:8])=[CH:23][CH:22]=1
Reactant: Clc1cnccn1
Reactant: CN(CC(c1ccc(O)cc1)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNCC(c1ccc(Br)cc1)c1ccc(Oc2cnccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
A solution of [2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (125 mg, 0.31 mmol), 2-chloropyrazine (35.2 mg, 0.31 mmol) and K2CO3 (213 mg, 1.54 mmol) in dimethylformamide (8 ml) was heated to 100° C. for 17 hours. Upon cooling, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was then treated with saturated HCl in diethyl ether (15 ml) and stirred at room temperature for 72 hours. The solvent was then removed under reduced pressure and the crude product was purified by Phenomenex_Strata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol to afford the desired product (82 mg). LC/MS: (PS-B3) Rt 3.17 [M+H]+384.
Reaction SMILES: CN1CCC[C@@H]1CO.[ClH:9].[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][CH:24]=1)[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]>O>[ClH:9].[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][CH:24]=1)[O:14][CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]
Reactant: CN1CCC[C@H]1COc1cccc(F)c1
Agent: CN1CCC[C@@H]1CO
Agent: Cl
Solvent: O
Product: CN1CCC[C@@H]1COc1cccc(F)c1

Procedure:
Following the procedures of Example 6, substituting (R)-1-methyl-2-pyrrolidinemethanol (Aldrich) for the (S)-1-methyl-2-pyrrolidinemethanol of Example 6, the title compound was prepared. MS: 210 (M+H)+. NMR (CDCl3) δ: 2.20-2.30 (m, 3H), 2.34-2.43 (m, 1H), 3.03 (s, 3H), 3.20-3.30 (m, 1H), 3.72-3.77 (m, 1H), 3.89-3.91 (m, 1H), 4.27 (dd, 1H, J=6, 11.5 Hz), 4.44 (dd, 1H, J=3, 11.5 Hz), 6.82-6.89 (m, 3H), 7.34-7.42 (m, 1H). Anal. Calcd for C12H17ClFNO.0.25 H2O: C, 57.60; H, 7.05; N, 5.59; Found: C, 57.86; H, 6.76; N, 5.59.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:5][CH2:6]2.[ClH:16]>O1CCOCC1.O>[OH:1][C@H:2]1[C@H:7]([Cl:16])[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:3]1
Reactant: Cl
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC2OC2C1
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@@H](Cl)[C@H](O)C1
Reaction time: 15 h

Procedure:
5.0 g (0.018 mol) of 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-piperidine are dissolved in 50 ml of dioxane and the solution is treated with 60 ml of 6 N hydrochloric acid. The slightly exothermic reaction is kept at room temperature by means of a water bath, and the reaction mixture is stirred for 15 hours, then diluted with water and extracted with 3 times 100 ml of methylene chloride. The organic phase is washed with 0.1 N sodium hydroxide solution and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and then evaporated to dryness, first under a water pump vacuum and then under a high vacuum, whereupon trans-3-hydroxy-4-chloro-1-(β,β,β-trichloroethoxycarbonyl)-piperidine is obtained in the form of a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1([C:14]([OH:16])=O)[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:26]>ClCCl>[Cl:1][C:2]1([C:14]([F:26])=[O:16])[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1
Reactant: O=C(O)C1(Cl)N=C(NC2CCCC2)C=CN1
Reactant: Fc1nc(F)nc(F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(F)C1(Cl)N=C(NC2CCCC2)C=CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a suspension of 5.24 (21.68 mmol) of the product prepared in step 3.1 in 140 mL of dichloromethane are added 3.02 mL (21.68 mmol) of triethylamine and then 2.75 mL (35.52 mmol) of cyanuric fluoride. The mixture is stirred at room temperature for 4 hours and the solution is diluted with 150 mL of dichloromethane. The organic phase is washed three times with 200 mL of ice-cold aqueous NaHCO3, dried over MgSO4, filtered and concentrated under vacuum. 5.2 g of the expected product are obtained in the form of an orange solid. Yield=98%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[C:5](Cl)=[O:6].[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH:29][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]4)=[C:2]([CH3:1])[CH:3]=3)[CH3:28])=[N:26][C:22]=2[CH:21]=1
Reactant: Cc1cc(C(=O)Cl)ccc1N1CCCN(C)CC1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCN(C)CC1

Procedure:
489 mg (1.61 mmol) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid chloride are placed together with 400 mg (3.96 mmol) TEA in 10 ml THF at ambient temperature and a solution of 433 mg (1.61 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine is added dropwise with stirring. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is combined with water and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on aluminium oxide (eluant: dichloromethane/methanol 100:1). The fractions evaporated down are treated with ethereal hydrochloric acid, after total concentration evaporated twice with ethyl acetate and diethyl ether and dried i. vac. at 70° C.
Reaction SMILES: CS(Cl)(=O)=O.[O:6]1[CH2:10][CH2:9][C@@H:8](O)[CH2:7]1.CCN(CC)CC.[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:32])[C:25]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(Cl)Cl.O>[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:32])[C:25]=1[N:26]1[CH2:31][CH2:30][N:29]([C@H:8]2[CH2:9][CH2:10][O:6][CH2:7]2)[CH2:28][CH2:27]1
Reactant: O[C@@H]1CCOC1
Reactant: Fc1cncc(Cl)c1N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cncc(Cl)c1N1CCN([C@H]2CCOC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
MsCl (393.3 mg, 265.7 μL, 3.433 mmol) was added to a solution of (3R)-tetrahydrofuran-3-ol (275 mg, 3.121 mmol) and Et3N (379.0 mg, 522.0 μL, 3.745 mmol) in DCM (5 mL) at 0° C. and the resulting solution stirred at RT overnight. The reaction mixture was diluted with water (5 mL) and DCM (5 mL) and the layers separated. The aqueous layer was extracted further with DCM (2×5 mL) and the combined organic extracts washed with saturated aqueous sodium hydrogen carbonate solution (1×5 mL), dried over MgSO4 and concentrated in vacuo. The residue was taken up in n-BuOH (5 mL) and 1-(3-chloro-5-fluoro-4-pyridyl)piperazine (1.010 g, 4.682 mmol) was added and the reaction mixture heated at 118° C. overnight. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by column chromatography on silica (24 g column, 0-100% EtOAc/petroleum ether). Product fractions were combined and concentrated in vacuo to leave (S)-1-(3-chloro-5-fluoropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine as an off white solid. MS (ES+) 288.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH2:11]2)[CH3:2].[CH2:16]([O:18][C:19]([C:21]1[C:22](Cl)=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=1)=[O:20])[CH3:17].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:16]([O:18][C:19]([C:21]1[C:22]([N:7]([CH:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][CH2:11]3)[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)CCNC1CC2CCC1C2
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(c1nc(SC)ncc1C(=O)OCC)C1CC2CCC1C2
Reaction time: 16 h
Yield: 62.2 %

Procedure:
3-(Bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester (1.5 g, 7.1 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.6 g, 7.1 mmol) were combined in CH2Cl2 (20 mL) and triethylamine (1.0 g, 10 mmol) was added. After 16 h, water (10 mL) was added the organic layer was separated, dried (MgSO4), and concentrated. Chromatography (10-50% EtOAc/hexanes gradient) provided 1.8 g of 4-[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester. Sodium (30 wt % dispersion in paraffin wax, 0.55 g, 7.2 mmol) was added to t-butanol (5.0 mL) at rt. After 30 minutes, a solution of 4[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.8 g, 4.4 mmol) in 20 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4), and concentrated. Recrystallization from i-PrOH provided 0.51 g of 8-bicyclo[2.2.1]hept-2-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 8-Bicyclo[2.2.1]hept-2-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.12 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 11.4 mg of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.21 (s, 1H), 8.59 (s, 1H), 7.52 (d, 2H, J=8.9 Hz), 6.87 (d, 2H, J=9.0 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.52-3.62 (m, 4H), 3.28 (br s, 2H), 2.98 (br s, 2H), 2.82 (s, 3H), 2.14-2.53 (m, 5H), 1.58-1.75 (m, 4H), 1.22-1.42 (m, 5H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39](=[O:42])(=[O:41])[NH2:40])=[CH:29][C:28]=2[F:43])[C:7](=[O:25])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:21]([F:24])([F:23])[F:22])[N:9]=1)[CH2:2][CH2:3][CH3:4].[F:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](O)=[O:48].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39](=[O:41])(=[O:42])[NH:40][C:47](=[O:48])[C:46]3[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=3[F:44])=[CH:29][C:28]=2[F:43])[C:7](=[O:25])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:21]([F:24])([F:22])[F:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1F
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2F)cc1F
Yield: 93 %

Procedure:
Reaction of 5-n-butyl-2,4-dihydro-4-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)methyl]-2-[5-(propionylamino)-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C) with 2-fluorobenzoic acid (3 equivalents), CDI (3 equiv), DBU (3 equiv), and DMAP (3 equiv) according to the method of Example 51 (as modified in Example 81) gave a a 93% yield of the title compound as a white, stiff foam, mp 119°-122° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 742 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[C:18]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH:17]=1)[O:10][C:11](=[O:15])[CH2:12][CH2:13][OH:14].[C:33]([O:37][C:38]([N:40]([C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][C:46]=1[O:54][CH2:55][CH:56]1[CH2:58][CH2:57]1)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:33]([O:37][C:38]([N:40]([C:45]1[CH:53]=[CH:52][C:48]([C:49]([O:14][CH2:13][CH2:12][C:11]([O:10][C@H:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[C:18]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:17]=2)[CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N+:4]([O-:32])=[CH:5][C:6]=2[Cl:31])=[O:15])=[O:50])=[CH:47][C:46]=1[O:54][CH2:55][CH:56]1[CH2:57][CH2:58]1)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(CCO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-hydroxypropanoyloxy)ethyl)pyridine 1-oxide (0.311 g, 0.632 mmol), 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoic acid (0.243 g, 0.632 mmol), and EDC (0.363 g, 1.895 mmol) in dry DCM (15 ml), DMAP (0.077 g, 0.632 mmol) was added and the resulting mixture was stirred at RT for 3 hours. The solvent was evaporated, and the residue was partitioned between EtOAc and a NaHCO3 sat. sol. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel column (DCM:MeOH:32% NH4OH=95:5:0.5) affording (S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)-methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.450 g, 0.523 mmol, 83% yield, MS/ESI+ 859.0 [MH]+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1)[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.Cl.Cl[CH2:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O1CCOCC1>[CH3:14][N:13]1[C:9]([C:3](=[N:2][O:1][CH2:17][C:18]2[N:19]=[C:20]([NH2:23])[S:21][CH:22]=2)[C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)=[CH:10][N:11]=[CH:12]1
Reactant: Cn1cncc1C(=NO)c1ccsc1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: C1COCCO1
Product: Cn1cncc1C(=NOCc1csc(N)n1)c1ccsc1
Temperature: 25 °C
Reaction time: 51 h
Yield: 11.1 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine (4.96 g, 23.9 mmol) and 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (4.88 g, 26.3 mmol) in acetonitrile (50 mL) were added cesium carbonate (13.5 g, 41.4 mmol) and potassium iodide (327 mg, 1.97 mmol). After stirring at room temperature for 51 h, 1,4-dioxane (25 mL) and potassium iodide (5.90 g, 35.5 mmol) were added and the mixture was stirred for 72 h at room temperature then at 70° C. for 3.5 h. The reaction mixture was filtered, the insolubles washed with acetone and methanol, and the filtrate concentrated in vacuo, diluted in ethyl acetate (50 mL), washed with water (2×30 mL), dried over MgSO4 and concentrated to dryness in vacuo. Purification of the residue on silica gel afforded 4-[({[(1-methyl-1H-imidazol-5-yl)(3-thienyl)methylene]amino}oxy)-methyl]-1,3-thiazol-2-amine [850 mg, yield 11%; HPLC/MS: m/z=320 (M+H); log P(HCOOH)=0.45].