Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:8]([CH2:29][CH3:30])[CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([CH2:20][NH2:21])=[C:15]3[S:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:13]([C:14]=23)=[N:12]1)[CH3:7].N1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:29]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([CH2:20][NH:21][S:2]([CH3:1])(=[O:4])=[O:3])=[C:15]3[S:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:13]([C:14]=23)=[N:12]1)[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CCn1nc2c3c(c(CN)ccc31)Sc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCn1nc2c3c(c(CNS(C)(=O)=O)ccc31)Sc1ccccc1-2
Temperature: 0 °C
Yield: 117.9 %

Procedure:
To a solution of methanesulfonyl chloride (0.172 g, 1.50 mmol) in CH2Cl2 (30 mL) is added the freebase of the compound of example 8 (0.51 g, 1.28 mmol)) and pyridine (0.4 mL) with stirring at 0° C. After the mixture is allowed to warm to ambient temperature over 5h CHCl3 (30 mL) and 2N NaOH (5 mL) is added to the mixture. The organic layers are separated, washed with water, dried over Na2SO4, and concentrated in vacuo to give the crude product. Purification by chromatography with 0.5% Et3N in CH2Cl2 gives 0.650 g of gum. Recrystallization from ether-methanol (90:10) gives the compound (0.460 g, 84%), mp: 120°-125° C. 1H NMR (CDCl3) 0.98 (6H; t), 2.58 (4H; q), 2.84 (3H; s), 2.92 (2H; t), 4.26 (2H; d), 4.38 (2H; t), 4.48 (1H; b), 6.90 (1H; d), 7.08-7.30 (4H; m), 8.06 (1H; m)ppm. MS m/z 431 (MH+). Anal. (C21H26N4O2S2.1/2H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)cc(C(=O)O)cc1I
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C(=O)Cl)cc1I
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To 3-chloro-5-iodo-4-methoxybenzoic acid (2.74 g), toluene (27 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.76 mL) were added to the solution, and then the mixture was stirred at 60° C. for 15 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (3.05 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([F:21])[CH:20]=1>>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:13])[CH:11]=[N:12][C:2]=1[O:22][C:17]1[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=1)[CH3:8]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: Oc1cc(F)cc(F)c1
Product: CCOC(=O)c1cc(F)cnc1Oc1cc(F)cc(F)c1
Yield: 23 %

Procedure:
The title compound was prepared from ethyl 2-chloro-5-fluoronicotinate and 3,5-difluorophenol in 23% yield following the procedure described in preparation 72.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][N:13](CC3C=CC=CC=3)[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CON=C1CN(Cc2ccccc2)CC12CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Yield: 87.9 %

Procedure:
t-butyl-6-benzyl-8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate was dissolved in 40 ml of methanol and thereto 4.0 g of 10% Pd-C was added. The resulting mixture was stirred for 2 hours under the pressure of hydrogen at 5° C., filtered and concentrated under the reduce pressure to give 1.3 g of the titled compound (yield: 87.9%).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:57])[CH2:46][N:47]1C=C2[C:49](C=CC=C2N)=[N:48]1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:57])[CH2:46][N:47]1[C:4]2[C:5](=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]3[N:19]=[C:18]([CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=4[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]3=[O:37])[CH:7]=[CH:8][CH:9]=2)[CH:49]=[N:48]1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)Cn1cc2c(N)cccc2n1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CC(C)(C)OC(=O)Cn1ncc2c(NC(=O)CN3N=C(C4CCCCC4)c4ccccc4N(CC(=O)C(C)(C)C)C3=O)cccc21

Procedure:
The title compound was obtained as the trifluoroacetate salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that (4-amino-indazol-2-yl)-acetic acid tert-butyl ester (prepared in two steps from 4-nitro-indazole) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (4-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-indazol-1-yl)-acetic acid tert-butyl ester (Example 130, step a), according to the method of Example 130, step b. 1H NMR (CDCl3) 10.04-9.95 (2H, br s), 9.06 (1H, s), 8.13 (1H, s), 7.53-7.20 (6H, m), 7.06 (1H, d, 6), 5.26 (2H, s), 4.80 (1H, d, 18), 4.63 (1H, d, 18), 4.29 (2H, s), 2.81-2.78 (1H, m), 2.07-1.67 (6H, m), 1.37-1.19 (13H, m). Found: C, 56.82; H, 5.42; N, 11.88%; C31H36N6O5.CF3CO2H.0.7H2O requires: C, 56.72; H, 5.53; N, 12.03%.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:13]=1[O:14][CH:15]1[CH2:18][N:17](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16]1>C(Cl)Cl>[Cl:11][C:12]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:13]=1[O:14][CH:15]1[CH2:18][N:17]([C:1]([Cl:4])=[O:2])[CH2:16]1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(F)cc2Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 9.0 g (0.09 mole) of phosgene in 200 mL of methylene chloride under nitrogen was treated with 12.5 g (0.09 mole) of anhydrous potassium carbonate and stirred for 30 min. The reaction mixture was cooled in an ice bath while 28 g (0.08 mole) of 3-(2-chloro-4-fluorophenoxy)-1-(diphenylmethyl)azetidine in 100 mL of methylene chloride was added dropwise. After stirring for 16 hr at ambient temperature the reaction mixture was cooled to 0° C. in an ice water bath and small pieces of ice were added to destroy the excess phosgene, being careful to control the evolution of carbon dioxide gas. When the evolution of gas ceased, the reaction mixture was decanted from the inorganic slurry, dried (filtered through Whatman PS paper) and concentrated in vacuo, 41.9 g. Upon standing, a semisolid residue formed and the solid was collected by filtration after trituration with hexane to obtain 13.2 g (62.5%). A sample was recrystallized from hexane for analysis yielding fine white crystals, mp 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O.[B-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu+]>[Cl:1][C:2]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: CSc1ccc(C(=O)Cl)c(Cl)c1
Agent: [Cu+]
Agent: [B-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: CSc1ccc(C=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A mixture of 2-chloro-4-(methylsulphenyl)-benzoyl chloride (1.0 g), triphenyl phosphine (2.47 g) and bis(triphenylphosphine)copper (I) borohydride (1.0 g) in acetone was stirred at 0° C. for 1 hour. Further bis (triphenylphosphine)copper (I) borohydride (1.5 g) was added and the mixture was stirred for 2 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and treated with copper (I) bromide (2.1 g). The filtrate was evaporated to dryness and the residue was purified by chromotography eluted with a mixture of ethyl acetate and hexane to give 2-chloro-4-(methylsulphenyl)benzaldehyde (0.83 g) as an off-white solid, m.p. 76°-77° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]#[C:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1.[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[C:32](I)[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:35]3[C:33](=[CH:32][CH:31]=[C:30]([F:29])[CH:36]=3)[NH:34][C:14]=2[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1
Reactant: CC[Si](C#CCCCC1(O)CCC(c2ccccc2)(N(C)C)CC1)(CC)CC
Reactant: Nc1ccc(F)cc1I
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC[Si](CC)(CC)c1[nH]c2ccc(F)cc2c1CCCC1(O)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-dimethylamino-4-phenyl-1-(5-triethylsilanyl-pent-4-inyl)cyclohexanol (525 mg, 1.31 mmol), 4-fluoro-2-iodoaniline (374 mg, 1.58 mmol), [1,3-bis-(2,6-diisopropyl-phenyl)imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI, 178 mg, 0.26 mmol) and sodium carbonate (694 mg, 6.6 mmol) was evacuated for 30 min (oil pump). It was then flushed with argon and absolute N,N-dimethylformamide (5 mL, previously flushed for 1 h with argon) was added by syringe via a Schlenk tube. The mixture was stirred for 18 h at 100° C. and changed colour to dark brown during this. The reaction mixture was then concentrated to low volume in a vacuum, the residue taken up several times in toluol (3×10 mL) and concentrated to low volume again in each case, distributed between water and ethyl acetate (20 mL each) and the phases separated again. The aqueous phase was extracted with ethyl acetate (2×30 mL), the combined organic phases were washed with 1 M sodium thiosulphate solution (30 mL) and saturated sodium chloride solution (50 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (1.10 g) was purified by means of flash chromatography (50 g, 20×3.0 cm) with chloroform/methanol (97:3).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[C:23]([O-:28])(=[O:27])[C:24]([CH3:26])=[O:25].[Na+].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:26]/[C:24](=[O:25])[C:23]([OH:28])=[O:27])=[CH:17][CH:16]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/C(=O)C(=O)O)cc1
Reaction time: 6 h
Yield: 44.5 %

Procedure:
A mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (2.9 g), sodium pyruvate (3.3 g), sodium carbonate (3.2 g), water (80 ml) and methanol (80 ml) was stirred for 6 hours under reflux. The reaction mixture was concentrated under reflux to about 1/3 of the initial volume. The concentrate was subjected to extraction with ethyl acetate. The aqueous layer was acidified with conc. HCl. Resulting crystalline precipitate was collected by filtration to obtain (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvic acid (1.6 g, 44%). Recrystallization from chloroform-methanol gave colorless needles, m.p.197-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[C:6]1=[O:17])=[O:4].[H-].[Na+].CI.[C:22](OCC)(=O)C>O1CCCC1.O>[CH3:22][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[C:6]1=[O:17]
Reactant: COC(=O)C1CCc2c(OC)cccc2C1=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCc2c(OC)cccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (3.9 g) in tetrahydrofuran (50 ml) were added NaH (0.73 g, 60% in oil) and then methyl iodide (3 ml) at 0° C. under N2. After being stirred for 1 hour at room temperature, the solution was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-methyl-2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (4.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: Br
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 10.12 g of 4′-chloropropiophenone, 0.1 ml of hydrobromic acid (48% aqueous solution) and 60 ml of acetic acid was cooled to 0° C. under a nitrogen atmosphere. 3.1 ml of bromine was added dropwise into the mixture, then, the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 14.34 g of 2-bromo-4′-chloropropiophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH3:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH3:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:37])[F:38]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1N(C)S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)S(C)(=O)=O

Procedure:
A mixture 4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg crude) in 4 M HCl in dioxane (12 mL) and water (4 mL) were heated at 100° C. for 18 h. The reaction mixture was concentrated to dryness under reduced pressure and subsequently neutralized aqueous NaHCO3 to pH to 5-6. The aqueous layer was extracted with EtOAc, the combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (20→80% gradient of MeCN-water) to provide 4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide as a solid. MS m/z: 582.0 (M+H).
Reaction SMILES: [CH2:1]([N:11]1[C:16](=[O:17])[CH:15]2[CH2:18][C:13]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)([CH2:14]2)[C:12]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(OCC)(=O)C.CCCCCC>COCCO.[Pd]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:13]23[CH2:14][CH:15]([CH2:18]2)[C:16](=[O:17])[N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]3=[O:28])=[CH:24][CH:23]=1
Reactant: CCCCCCCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: COCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-n-decyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 81.5°-82.5° (from ethyl acetate/hexane).
Reaction SMILES: C(OC(=O)NC[C:9](=[O:29])[NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=2)[CH:14]=[CH:13][N:12]=1)(C)(C)C.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:45])C=CC=CC=1.[C:55]([N:62]1[CH2:65][CH2:64][CH:63]1O)([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>C1COCC1>[C:58]([O:57][C:55]([N:62]1[CH2:65][CH:64]([O:45][C:9](=[O:29])[NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH2:63]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CNC(=O)OC(C)(C)C)c2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNc1ccc(Oc2ccnc(NC(=O)OC3CN(C(=O)OC(C)(C)C)C3)c2)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 70 %

Procedure:
To a suspension of acid 1 (1 eq.) in dry THF (10 mL) at 0° C. was added triethylamine (3.0 eq.) and the resulting reaction was maintained at 0° C. for 45 min to afford a homogenous solution. Diphenylphosphoryl azide (DPPA, 1.1 eq) was added and the reaction was maintained o/n allowing the cooling bath to expire. The reaction was concentrated and the resulting residue dissolved in CH2Cl2. The organic portion was washed with saturated NaHCO3 (3×) and the combined aqueous phases were extracted with CH2Cl2. The combined organic portions were dried (MgSO4), filtered, and concentrated. The remaining residue was suspended in toluene. To this suspension was added N—BOC azetidin-2-ol (1 eq) and the reaction mixture was heated to and maintained at 100° C. for 1 h. The reaction was then allowed to cool to rt and concentrated. The residue was dissolved in CH2Cl2 and washed with saturated Na2CO3 (3×). The combined aqueous phases were extracted with CH2Cl2 and the combined organic layers were washed with Na2CO3 and brine, dried (MgSO4), and evaporated. The crude residue was adsorbed onto SiO2 and purified by flash chromatography (9:1, 4:1, 2:1, 1:1 hexanes-EtOAc) to furnish 625 mg (70%) of a light orange solid as 2: 1H NMR (300 MHz, CDCl3) δ 9.32 (br, s, 1 H), 8.17 (d, J=6.0 Hz, 1 H), 8.06 (br dd, J=5.0, 10.2 Hz, 1 H), 7.96 (d, J=2.8 Hz, 1 H), 7.52 (d, J=2.5 Hz, 1 H), 7.30 (dd, J=2.8, 9.2 Hz, 1 H), 6.93 (d, J=9.2 Hz, 1 H), 6.57 (dd, J=2.5, 6.0 Hz, 1 H), 5.18 (dddd, J=4.4, 4.4, 6.9, 6.9 Hz, 1 H), 4.25 (ddd, J=0.8, 6.9, 10.1 Hz, 2 H), 3.94 (ddd, J=0.8, 4.4, 10.1 Hz, 2 H), 3.07 (d, J=5.2 Hz, 3 H), 1.43 (br s, 9 H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>[OH-].[Na+].O1CCOCC1>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCOC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 34.2 g (217.5 mmol) of trans 4-aminomethylcyclohexanecarboxylic acid (Aldrich) in 217 mL of 2M aq. NaOH and 217 mL of dioxane was cooled to 15° C. To this solution was added 25 mL (235 mmol) of allyl chloroformate (Aldrich) in a slow stream. After the addition, the cold bath was removed, and the solution was stirred overnight at ambient temperature. The reaction mixture was poured slowly into a rapidly stirred mixture of 1L of 1M aq. citric acid and ice. The resulting mixture was stirred for 0.5 h and the precipitate collected by filtration, washed with water, and dried to a constant weight of 49.3 g (94%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[OH:38][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[N:10][C:9]3=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp>205° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.70 (m, 9 H), 3.70-4.00 (m, 7 H), 4.95 (brs, 1 H), 6.64-6.94 (m, 3 H), 7.01(d, J=8.9 Hz, 2 H), 7.27-7.30(m, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 262.0 ((M+2H)2+, 100%); 523.0 (MH+, 10%); HRMS Calcd. for C27H35N6O3S (MH+): 523.2491. Found: 523.2511.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C[O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=[O:18]>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:23][C:24]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 77 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.033 g, 0.14 mmol) obtained in Step C of Preparation Example 27 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 77%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=C=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([NH:19][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:7])=[O:18])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCCCCN=C=O
Reactant: NCc1ccccc1
Product: CCCCCNC(=O)N1CC(=NOC)C[C@H]1C(=O)NCc1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and benzylamine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=361.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[CH3:25][C:26]([NH2:29])([CH3:28])[CH3:27]>>[C:26]([NH:29][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:14][C:15]=12)=[O:24])([CH3:28])([CH3:27])[CH3:25]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 67 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and 2-methylpropan-2-amine to yield the title compound as a white solid (23 mg, 67% yield). MS (apci) m/z=383.1 (M+H).