Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.S([CH2:40][N+:41]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C>[C:40]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1)#[N:41]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: N#CC1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To a solution of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (384 mg) and tosylmethyl isocyanide (430 mg) in 1,2-dimethoxyethane (4 ml) was added dropwise a solution of potassium tert-butoxide (448 mg) in a mixture of 1,2-dimethoxyethane and tert-butanol (1:1, 2 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 30 minutes. Then, it was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude product was crystallized from diethyl ether to give yellow crystals of 3-[2-(2-cyanocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.Br[CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: C=C(C)CCBr
Reactant: CC(C)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CCOc1ccc(Br)cc1C(C)C
Temperature: 60 °C

Procedure:
4-Bromo-2-isopropylphenol (897 mg, 4.17 mmol) was dissolved in DMF (4.17 mL) and 4-bromo-2-methylbut-1-ene (1.24 g, 8.34 mmol) was added followed by K2CO3 (1.15 g, 8.34 mmol). The reaction mixture was heated to 60° C. overnight, cooled to room temperature, and diluted with Hexanes:EtOAc (1:1). Water was added and the organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography, eluting with 0-15% EtOAc/Hexanes to give the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:25][C:26]1([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:29][NH:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:28]3[CH2:29][C:26]([CH2:30][N:31]([CH3:33])[CH3:32])([F:25])[CH2:27]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C)CC1(F)CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 1.8 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g, 1.0 eq.) was dissolved in DCM (10 mL). The reaction mixture was cooled to −60° C., at which temperature 1-(3-fluoroazetidin-3-yl)-N,N-dimethylmethanamine (0.22 g, 1.2 eq) and T3P (50% in EtOAc) (1.08 g, 1.2 eq.) were added, followed by DIPEA (0.36 g, 2 eq.). The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography to give 12 mg of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino)methyl)-3-fluoroazetidin-1-yl)prop-2-en-1-one (3% yield). 1H NMR (400 MHz, CDCl3) δ=9.75 (s, 1H), 8.62 (s, 2H), 7.94 (s, 1H), 7.24-7.21 (d, J=10.8 Hz, 1H), 5.69-5.66 (d, J=10.8 Hz, 1H), 4.37-4.25 (m, 2H), 4.22-4.15 (m, 2H), 2.82-2.76 (d, 2H), 2.35 (s, 2.35, 1H); LCMS for C19H19F7N5O [M+H]+ 466.4 found 466.3 at retention time 2.263 min
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=O.S([O-])([O-])(=O)=O.[Ca+2].C(O)(=O)C>C(O)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:13]([CH3:15])=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=2)[CH:6]=[N:7]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1ccc2cn[nH]c2c1
Reaction time: 24 h
Yield: 84.5 %

Procedure:
To a suspension of 6-aminoindazole (40.0 g, 0.30 mol) in absolute ethanol (500 ml) was added ethyl acetoacetate (70.37 g, 54 mol), calcium sulfate (CaSO4) (20 g) and acetic acid (2 ml). The reaction mixture was heated to reflux and after 24 hours more calcium sulfate (10 g) and ethyl acetoacetate (19 ml) was added and the reflux continued for another 24 hour period. It was necessary to add more CaSO4 (5 g) and ethyl acetoacetate (10 ml) and to reflux the reaction mixture for an additional 24 hours to complete the conversion of 6-aminoindazole to product. The solid was removed by filtration and the filtrate subjected to rotary evaporation. Ethanol was added and the slurry cooled in a refrigerator. The solid was collected by filtration, washed with hexanes and dried in a vacuum oven to give the cyclization precursor ethyl 3-(indazol-6-ylamino)but-2-enoate as a light brown solid (62.19 g, 84%).
Reaction SMILES: [NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[CH:5]([C:10]3[N:14]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:18][CH:17]=4)[N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.N1C=CC=CC=1.[C:38]1([CH2:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:38]1([CH2:44][C:45]([NH:1][CH:2]2[C:30](=[O:31])[N:4]3[CH:5]([C:10]4[N:14]([CH2:15][C:16]5[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)=[CH:20][CH:21]=5)[N:13]=[N:12][N:11]=4)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]23)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
To a stirred solution of 189 mg of 6-amino-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam in 4 ml of chloroform, is added, at ambient temperature, 0.038 ml of pyridine followed by 0.057 ml of phenylacetyl chloride. Stirring is continued for a further 45 minutes, and then the reaction mixture is diluted with 25 ml of chloroform and then washed with water. The organic phase is dried using anhydrous magnesium sulfate and then evaporated in vacuo. The residue is 209 mg (86% yield) of 6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam. The NMR spectrum (in CDCl3) shows absorptions at 7.50-6.70 ppm (multiplet, aromatic hydrogens), 6.4 ppm (doublet, amide hydrogen), 5.80-5.20 ppm (multiplet, benzyl hydrogens and C-5 and C-6 hydrogens), 5.10 ppm (singlet, C-3 hydrogen), 5.05 ppm (singlet, benzyl hydrogens), 3.60 ppm (singlet, phenylacetyl methylene hydrogens), 1.30 ppm (singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: C(OP(Cl)(OCC)=O)C.[CH3:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13](=O)[C:12]1=[O:22].[N+:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[C-:24].O>CN(C)C=O>[CH3:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:24]=[N:23][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]2[C:12]1=[O:22]
Reactant: Cn1c(=O)c(=O)[nH]c2ccccc21
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CCOP(=O)(Cl)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1c(=O)n(C)c1ccccc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
6.2 ml of diethylchlorophosphate was added to a mixture of 5.3 g of 1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline and of 4.5 g of K-t-butoxide in 50 ml dimethyl formamide (DMF) at room temperature. The resulting mixture was heated until it formed a solution and was then cooled to -30° C. A -30° C. cold mixture of 4.8 g of K-t-butoxide and 4.5 ml of ethyl isocyanoacetate in 20 ml of dry DMF was added to this solution. The resulting mixture was stirred for one hour at room temperature. Then 100 ml of water was added and the mixture was filtered. The resulting residue was crystallized leaving 2.5 g of the title compound. M.p. 218.5°-219.8° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]O.S(=O)(=O)(O)O.[F:10][C:11]1[CH:25]=[CH:24][C:14]([CH:15](O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:15]([C:14]1[CH:24]=[CH:25][C:11]([F:10])=[CH:12][CH:13]=1)[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: OCCCl
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1ccc(C(CCCl)c2ccc(F)cc2)cc1
Yield: 95 %

Procedure:
To a solution of 29,3 g of 2-chloroethanol in toluene 2 ml of concentrated sulphuric acid were added, after which 50 g of 4,4'-difluorobenzhydrol were added under stirring. The mixture was refluxed for 2 h, cooled and more toluene added. The organic phase was washed successively with water, aqueous sodium carbonate, and water and then dried. The solvent was evaporated to give 65 g of a crude product which was distilled to obtain 57.5 g (89,5%) of [1-(2-chloroethyl)]-bis-(4-fluorophenyl)methane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>CN(C=O)C>[CH2:16]([N:15]1[C:11]([O:10][C:4]2[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:3]=2)=[CH:12][CH:13]=[N:14]1)[CH3:17]
Reactant: CCn1nccc1Oc1cc(Br)cnc1C#N
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1C#N
Reaction time: 1 h
Yield: 93.3 %

Procedure:
5-Bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.1 g, 55 mmol) and cesium carbonate (17.9 g, 55 mmol) were combined with DMF (160 ml), and pyridine-2-thiol (6.1 g, 55 mmol) dissolved in DMF (40 ml) was added dropwise over 30 minutes. The mixture was agitated for 1 hour, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified over silica gel (20-35% ethyl acetate/hexanes) to afford 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (16.6 g, 93% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C)nc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Commercially available 6-Methyl-2-nitro-pyridin-3-ol (Aldrich) (5.09 g, 33 mmol) in acetone (50 mL) was treated with K2CO3 (5.47 g, 39.6 mmol) and MeI (3.09 mL, 49.5 mmol). The orange suspension was heated to 50° C. for 90 hours. After evaporation of the solvent in vacuo the crude mixture was treated with 1N NaOH (50 mL) and extracted with EtOAc (2×50 mL) the combined organic phases was washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. 3-Methoxy-6-methyl-2-nitro-pyridine was obtained as a yellow solid.
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1
Reactant: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cc(CO)ccn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-ethanone (340 mg, 1.28 mmol) in dry THF (5 mL) was treated at 0° C. with TBAF (1.9 mL of a 1M solution in THF, 1.90 mmol). The reaction mixture was stirred at 0° C. for 5 min and at rt for 1 h30. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (5:1 to 1:3 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.10. LC-MS-conditions 02: tR=0.40 min; [M+H]+=152.24.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C.Cl>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)CC1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of 3-(trifluoromethyl)benzenesulfonyl chloride (1 eq) in dichloromethane (1.6 ml/mmol) was added dropwise to a cooled solution (0° C.) of methyl 2-(piperidin-2-yl)acetate hydrochloride (1.1 eq) in dichloromethane (40 ml/mmol) and triethylamine (2.5 eq). The mixture was stirred for 90 min at 25° C., after which the reaction was completed (thin-layer chromatographic analysis). Hydrogen chloride solution (0.5 mol/l, 2 ml/mmol) was added and the mixture was stirred for 15 min. The organic phase was separated off, washed with water, dried over sodium sulfate and concentrated to small volume under vacuum. Yield: 80%
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.C(OCC)(=O)C>O1CCOCC1>[C:23]1([CH2:22][CH2:21][CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:9]3[C:8]([NH2:7])=[CH:12][O:11][N:10]=3)=[CH:14][CH:15]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCCCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1conc1-c1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
{3-[4-(3-Phenyl-propoxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (54 mg, 0.137 mmol) was dissolved in dioxane (9 mL) and treated with conc. HCl (1.5 mL). After stirring for 12 h at rt the reaction mixture was quenched with 10 mL of satd aqueous NaHCO3. The organic layer was separated and dried over Na2SO4. Filtration followed by removal of volatiles under reduce d pressure gave crude product. 3-[4-(3-Phenyl-propoxy)-phenyl]-isoxazol-4-ylamine (22 mg, 55%) was isolated as a white solid by column chromatography (30% ethyl acetate in hexanes). HRMS: 295.144 (M+1).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@:11]1([F:27])[CH2:25]I)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O-])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Na+].C1OCCOCCOCCOCCOCCOC1.O>CS(C)=O>[C:1]([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@@:11]1([F:27])[CH2:25][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CI)[C@H]1OC(=O)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@](F)(CC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Chiral (2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,4-difluor-O-2-(iodomethyl)-4-methyl-tetrahydrofuran-3-yl benzoate (0.56 g, 1.15 mmol), sodium benzoate (0.825 g, 5.73 mmol) and 18-crown-6 (0.03 g, 0.115 mmol) were suspended in DMSO (20 mL), the solution was heated to 100° C. and stirred under nitrogen atmosphere for 18 h, then cooled to r.t., water (30 mL) was added into it, the mixture was extracted by EA (30 mL×3), the organic layer was washed with H2O, brine and H2O, removed solvent by reduced pressure, the residue was purified by silica gel column chromatography (PE:EA=1:2) to afford the title compound as a colorless oil (0.34 g, 61%).
Reaction SMILES: Cl.CO.[CH2:4]([NH2:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][C:13]1([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C([BH3-])#N.[Na+].Cl>CO>[CH2:4]([NH:11][CH:16]1[CH2:17][CH2:18][C:13]([CH3:12])([C:20]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C1(C)CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C)CCC(NCc2ccccc2)CC1

Procedure:
5N hydrochloric acid-methanol was added to a solution of 19.6 ml of benzylamine in 75 ml of methanol under ice-cooling, neutralizing the solution. Then, 5.1 g of methyl 1-methyl-4-oxo-1-cyclohexanecarboxylate and 1.13 g of sodium cyanoborohydride were added to the mixture solution. The solution was reacted at room temperature for 26 hours. After reaction, concentrated hydrochloric acid was added to the reaction solution, adjusting the pH value to 2 or less. The solution was washed three times with 30 ml of methylene chloride. Further, a 2N aqueous sodium hydroxide solution was added to the aqueous layer formed, adjusting the pH value to 10 or more. The solution was extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo. The oily substance, thus obtained, was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=4:1, the solvent was removed in vacuo, yielding 3.1 g of methyl 4-(N-benzylamino)-1-methyl-1-cyclohexanecarboxylate as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[CH:3]1.N1C=CN=C1.[CH2:16]([Si:18](Cl)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.O>[CH2:8]([C:4]1[C:5](=[O:7])[CH2:6][CH:2]([O:1][Si:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:3]=1)[C:9]#[CH:10]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CCC1=CC(O)CC1=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC1=CC(O[Si](CC)(CC)CC)CC1=O
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.84 mmole) of the title compound of Example B in 4 ml of dimethylformamide was treated successively with 200 mg (3 mmole) of imidazole and 300 mg (2 mmole) of triethylsilyl chloride. After stirring for thirty minutes, the reaction mixture was diluted with water, washed with diethyl ether, dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was chromatographed on silica gel to give 0.37 g of the title compound as an oil. Structure assignment was confirmed by the proton nmr spectrum: 2.13 (t, J=2 Hz, ≡C--H), 3.08 (mult, --CH2 --C≡), 4.90 (mult C-11), ##STR9##
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:23][C:22]3[CH:25]=[CH:26][C:19]([OH:18])=[CH:20][CH:21]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 65 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (4.40 g) was suspended in 125.00 mL of ethanol and 4-hydroxybenzaldehyde (4.273, 1.5 eq.) and piperidine (0.50 eq, 865 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (4.00 g, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16]1([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH:28]=O)[CH2:19][CH2:18][CH2:17]1)=[O:15].N1CCCC1>CO>[CH3:12][O:13][C:14]([C:16]1([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2/[CH:28]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:19][CH2:18][CH2:17]1)=[O:15]
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C1(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CCC1
Temperature: 80 °C
Yield: 23.9 %

Procedure:
To the mixture of 6-chlorooxindole (10 g, 60 mmol) and 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester (18 g, 67 mmol) in methanol (100 mL) was added pyrrolidine (4.5 mg, 63 mmol) dropwise. The mixture was then heated at 80° C. for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound (6 g).
Reaction SMILES: [Na].[N+:2]([C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl>O>[N+:2]([C:5]1[C:13]2[N:12]=[N:11][N:10]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cccc2[nH]nnc12
Agent: [Na]
Solvent: O
Product: O=[N+]([O-])c1cccc2c1nnn2SC(Cl)(Cl)Cl

Procedure:
A solution of 10.2 grams of the sodium salt of 4-nitrobenzotriazole, 6 milliliters of trichloromethylsulfenyl chloride and 100 milliliters of water is stirred at 5° C. for 1 hour. The brown solid is collected by filtration and washed with ethyl ether. The crude product weighs 9.3 grams (51%) and recrystallized from carbon tetrachloride, m.p. 136.5°-137.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1(Br)[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH3:13])=[O:6])[CH3:2].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH3:13])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)C1(Br)CCOC1OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCOC1OC
Yield: 98.1 %

Procedure:
Ethyl-2-(3-bromo-2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (8.5 g) was dissolved in Ethanol (85 ml). Triethyl amine (3.66 g) was added to the reaction mass. 5% Palladium on Carbon (0.85 g) was added and reaction was hydrogenated at 4-5 kg pressure of Hydrogen for 8 hrs. Reaction mass was filtered through hyflow and concentrated to residue. This residue was slurried in methyltert-butylether (42 ml) and filtered to remove triethylamine HBr salt. Filtrate was concentrated to get oily residue of Ethyl-2-(2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (yield 6.0 g).