Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[C:6]([NH:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[NH:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: CNc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methylamino-benzoic acid methyl ester (0.22 g, 0.35 mmol) in MeOH (4 mL) and THF (12 mL) was added an aqueous solution (1N) of NaOH (7.5 mL, 7.5 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water, and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methylamino-benzoic acid as a off white solid (Yield, 18 mg, 8%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:20][N:18]([CH3:19])[CH:17]=[C:10]([CH3:11])[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=1)=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Product: CC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 25 g. of m-trifluoromethylpropiophenone and 25 ml. of dimethylformamide dimethylacetal is refluxed overnight and then evaporated to an oil. The oil is dissolved in hexane and the solution is refrigerated giving crystals of the desired product, m.p. 53°-55° C.
Reaction SMILES: [C:1]([C:5]([CH3:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH2-].[Na+].[C:10](OCC)(=[O:12])[CH3:11]>>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5](=[O:6])[CH2:7][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(C)=O
Agent: [NH2-]
Agent: [Na+]
Product: CC(=O)CC(=O)C(C)(C)C

Procedure:
Methyl t-butyl ketone was condensed with ethyl acetate in the presence of sodamide to yield 5,5-dimethyl-2,4-hexanedione. This material was reacted with phosphorus pentachloride to yield the divinyl chloride, which was in turn dehydrohalogenated with sodamide to give 5,5-dimethyl-1,3-hexadiyne. This alkyne was then dimerized using the procedure of Hay (see e.g. Hay, A. S., J. Org. Chem. 27, 3320 (1962) ), using copper(I) chloride-tetramethylethylenediamine (TMEDA) complex as the catalyst, to yield the desired t-butyl endcapped tetrayne. The tetrayne melted at 99° C. and decomposed between 130° C. and 140° C. It is also stable to moderate pressures; exposure to 40 kbar pressure for one hour caused no changes in the IR spectrum, and at 60 kbar only about 2% graphitization was seen.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][CH2:15][C:16]#[N:17])(=[O:13])=[O:12])([O:3]C)=O.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30]Cl>ClCCl>[C:16]([C:15]1[N:14]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[S:11](=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]=1[OH:3])#[N:17]
Reactant: COCCOCCl
Reactant: COC(=O)c1ccccc1S(=O)(=O)NCC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCN1C(C#N)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of o-carbomethoxy-N-cyanomethylbenzenesulfonamide (6.25 g) in dichloromethane (50 ml) was added triethylamine (2.5 g) and then beta-methoxyethoxymethyl chloride (3.12 g) at 5°-10° C. After being stirred for 1 hour at room temperature, the mixture was washed with water, dried over sodium sulfate and concentrated. To the resulting oil was added toluene (33 ml) and then 28% sodium methoxide in methanol (4.6 ml) and stirring was continued for an additional 16 hours at room temperature. The mixture was extracted with water (50 ml) and the aqueous layer was acidified to pH 2 with 6N HCl and extracted with dichloromethane. The resulting organic layer was washed with water, dried over sodium sulfate and concentrated to a viscous oil, which was submitted to silica gel column chromatography (SiO2, 100 g) and eluted with a mixed solvent (CH2Cl2 :CH3OH 4:1) to give the title product as a viscous oil.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1.[B:27](OC)([O:30]C)[O:28]C>CCOCC>[B:27]([C:15]1[CH:14]=[C:13]([O:12][CH3:11])[CH:26]=[CH:25][C:16]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])([OH:30])[OH:28]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: COc1ccc(NC(=O)OC(C)(C)C)c(B(O)O)c1
Temperature: -20 °C
Reaction time: 5 h
Yield: 54.8 %

Procedure:
A solution of t-butyllithium in pentane (1.70M, 200 mL, 340 mmol, 2.50 equiv) was added via cannula to a solution of tert-butyl 4-methoxycarbanilate (30.4 g, 136 mmol, 1 equiv) in ether (500 mL) at -20° C., producing a cloudy yellow solution. After stirring at -20° C. for 5 h, trimethyl borate (46.3 mL, 408 mmol, 3.00 equiv) was added. The resulting viscous solution was swirled by hand for 5 min, then was allowed to warm to 23° C. and was held at that temperature for 12 h. The product solution was partitioned between saturated aqueous ammonium chloride solution (500 mL) and ethyl acetate (500 mL). The aqueous layer was separated and further extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The product was purified by flash column chromatography (2.5% methanol-dichloromethane initially, grading to 10% methanol-dichloromethane) to provide the tert-Butyl 2-Borono-4-methoxycarbanilate (8) as a yellow powder (19.9 g, 55%). ##STR20##
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:9][N:10]=1)(=[O:3])[CH3:2].[Na].[CH3:19]I>C(O)C>[C:1]([N:4]([CH3:19])[NH:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)NNc1nnc(-c2ccccc2C)s1
Agent: [Na]
Solvent: CCO
Product: CC(=O)N(C)Nc1nnc(-c2ccccc2C)s1
Yield: 68.7 %

Procedure:
2-(2-Acetylhydrazino)-5-(2-methylphenyl)-1,3,4-thiadiazole (6.30 g) was added to a stirred solution of sodium (0.57 g) in ethanol (63 ml) at room temperature. After 15 minutes methyl iodide (7.10 g) was added and the solution kept at room temperature for 31/2 hours. The solvent was removed in vacuo and the residue chromatographed on a silica column (315 g) using mixtures of methanol and chloroform, finally eluting with 5% methanolchloroform. The resultant product was crystallised from ethyl acetate to give 2-(2-acetyl-2-methylhydrazino)-5-(2-methylphenyl)-1,3,4-thiadiazole (4.57 g) m.p. 106°-8°.
Reaction SMILES: O[CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30]>[Pd].C(O)(=O)C>[CH2:2]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)c1ccccc1)OCC2c1ccc(C(C)C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(Cc2ccccc2)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 66.9 %

Procedure:
A solution of N-(7-(hydroxy(phenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (512 mg, 1.05 mmol) obtained in Example 94 and 10% palladium on carbon (water content: 50%, 50 mg) in acetic acid (20 mL) was stirred at 80° C. for 1.5 hours under hydrogen atmosphere. The catalyst was removed and the reaction solution was concentrated under reduced pressure. Water was added to the residue and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to obtain 330 mg (yield: 67%) of the title compound. Melting point: 153-154° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)c1C

Procedure:
118 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(2,3-dimethylphenyl)piperazine (52 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1C=CC=CC=1>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH2:14][O:15][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(CO)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: CC(COC(=O)c1ccccc1)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 75 %

Procedure:
1 g of β-[4-(4-Trifluoromethylphenoxy)phenoxy]-propanol and 0.25 g of pyridine were dissolved in 10 ml of benzene, and 0.45 g of benzoyl chloride was added slowly to the solution while cooling. After completion of the addition, the mixture was allowed to react at a temperature of 20° C. for 1 hour, and the reaction mixture was poured into an appropriate amount of water. The benzene layer was separated and, after drying, benzene was removed to obtain 1 g of the desired product (nD20 1.541) as an oily substance.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[CH2:19][C@H:18]2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:31]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[CH2:19][C@H:18]2[N:20]([CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)CN(C(=O)OC(C)(C)C)[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.5 equiv of NaH in dry DMF (10 vols) at 0° C. was added a solution of ter-butyl(trans)-2-[4-(benzyloxy)phenyl]cyclopropylcarbamate (Intermediate C, 1 equiv) in dry DMF (2 vols) and stirr for 30 mins. Then, added was a solution of 1-(chloroacetyl)-4-methylpiperazine (1.5 equiv) in dry DMF (10 mL) at 0° C., stirred for 1 h at 0° C. to RT. The progress of the reaction was monitored by TLC. After completion, reaction mixture was poured into ice water and extracted with EtOAC. The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purifying by preparative HPLC to get tert-butyl(trans)-2-[4(benzyloxy)phenyl]cyclopropyl(2-(4-methylpiperazin-1-yl)-2-oxoethyl)carbamate derivative.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[O:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[O:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)co1
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5coc(C(C)C)n5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((2-isopropyloxazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.070 g, 0.16 mmol), EtOH (3 mL), and p-anisaldehyde (0.025 g, 0.18 mmol) in EtOH (1 mL) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.49 mL, 0.49 mmol). The reaction mixture was heated at 85° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on preparative silica TLC plates, which were eluted with dichloromethane/ethyl acetate (v/v; 1:1). The title compound was isolated as a pale yellow solid (0.019 g, 23%) after trituration with diethyl ether; 1H-NMR (500 Mz, DMSO-d6): δ 1.27 (d, J=7 Hz, 6H, iPr—CH3), 2.65 (m, 4H, piperazine N(CH2)2), 3.05 (m, 1H, iPr—CH), 3.44 (s, 2H, NCH2), 3.65 (m, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OMe), 7.10 (d, J=7.5 Hz, 2H, ArH), 7.86 (s, 1H, oxazole 5-H), 8.13 (d, J=9.0 Hz, 2H, ArH), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.30 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.45 min—511/514 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 511.1457, calculated for C24H28BrN6O2 (M+H)+: 511.1457.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:26])=[O:25])[CH2:22][CH2:23]2)[CH:13]=1
Reactant: O=S(=O)(CC(CCc1ccccc1)NO)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CCc1ccccc1)CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (19 ml) was added directly to formic acid (76 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1-(6-chloropyrimidin-4-yl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine (17.2 g) in tetrahydrofuran (85 ml) was added in portions, to the above solution at 27° C. over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (200 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in ethanol, a solid separated and the mixture was stirred for 2 days. The solid was collected by filtration, slurry washed with diethyl ether (100 ml), and dried to give N-[1-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamide as a colourless solid (12.8 g). mp 155-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:29])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)[O:14]1>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:18][C:17]1([CH3:19])[C:13]([CH3:12])([CH3:29])[O:14][B:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N:3]=3)=[O:25])=[CH:22][CH:21]=2)[O:16]1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)cc2)OC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1(C)OB(c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C

Procedure:
To the stirred solution of 2-amino-4-(trifluoromethyl)pyridine (10.79 g, 66.6 mmol) and 4-dimethylaminopyridine (7.39 g, 60.5 mmol) in Acetonitrile (125.00 ml) was added a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (16.12 g, 60.50 mmol) in Acetonitrile (75.00 ml) dropwise at room temperature. The solution turned into suspension after about half an hour and was stirred at r. t. overnight. The reaction mixture was concentrated and partitioned between 250 ml 0.2 N HCl and 250 ml CH2Cl2. The organic phase was separated and washed with 2×250 ml 0.2N HCl. The organic phase was dried over MgSO4 and evaporated to dryness. The crude was purified on RediSep 220 g silica cartridge and eluted with 1 lt Hexane, 4 lt 10% EtOAc/Hexane, 4 lt 20% EtOAc/Hexane gave white solid product 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide. 1HNMR (CD3Cl, 500 MHz, δ): 8.83 (1H, br), 8.71 (1H, s), 8.45 (1H, d), 7.93 (4H, m), 7.30 (1H, d), 1.38 (12H, s).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(OCC)(=O)CC(C)=O>>[OH:5][CH:1]([CH2:2][CH2:3][CH3:4])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCC(=O)CC(=O)OCC
Solvent: CCOC(=O)CC(C)=O
Product: CCCC(O)CC(=O)OCC
Yield: 48 %

Procedure:
Ethyl 3-hydroxycaproate was prepared following the procedure as described in step 1) of Preparation Example 2, except for that ethyl butyrylacetate was used to replace for ethyl acetoacetate. Yield 48%.
Reaction SMILES: [ClH:1].[CH2:2]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[OH:10])[CH2:3]1.C(N(CC)CC)C.C(O)(=O)C.C(OC([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH:37]=O)[C:31](=[O:39])[CH:30]1[CH3:40])=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:1].[ClH:1].[OH:10][C@@H:5]1[CH2:6][N:7]([CH2:37][CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][NH:29][CH:30]([CH3:40])[C:31]2=[O:39])[CH2:8][CH2:9][C:4]21[CH2:3][CH2:2]2
Reactant: O[C@@H]1CNCCC12CC2
Reactant: CC1C(=O)N(CCC=O)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Reaction time: 2 h
Yield: 282.2 %

Procedure:
To a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 25; 0.03 g, 0.2 mmol) in dichloromethane (1 ml) was added triethylamine (0.03 ml, 0.2 mmol) and acetic acid (0.02 ml, 0.4 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.06 g, 0.24 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.06 g, 0.26 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4 N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.2 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (4 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=480.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[ClH:15].Br[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:15].[ClH:15].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([O:14][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: BrCc1cccnc1
Reactant: Cc1csc(Nc2ncccc2O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccnc2)n1
Yield: 99.7 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 75 mg, 0.362 mmol), 3-(bromomethyl)pyridine hydrochloride (75.4 mg, 0.362 mmol) and potassium carbonate (175 mg, 1.27 mmol) were reacted according to Example 3, Step B, to provide N-(4-methylthiazol-2-yl)-3-(pyridin-3-ylmethoxy)pyridin-2-amine dihydrochloride (67 mg, 49.9% yield) as a tan solid. 1H NMR (d6-DMSO) δ 10.15 (bs, 1H), 8.82 (s, 1H), 8.57 (d, 1H), 8.07 (m, 1H), 7.88 (dd, 1H), 7.46 (m, 2H), 6.92 (dd, 1H), 6.58 (s, 1H), 5.29 (s, 2H), 2.24 (s, 3H). Mass spectrum (apci) m/z=299 (M+H-2HCl).