Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH2:26][CH2:25][C:22]2([O:24][CH2:23]2)[C:21](=[O:27])[CH:20]=1.[Cl-].[NH4+]>C(OCC)C.C1(C)C=CC=CC=1>[OH:27][C:21]1([CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:20]=[C:19]([O:18][CH3:17])[CH2:26][CH2:25][C:22]21[O:24][CH2:23]2
Reactant: C#CCCCc1ccccc1
Reactant: COC1=CC(=O)C2(CC1)CO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC1=CC(O)(C=CCCCc2ccccc2)C2(CC1)CO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
74 ml (0.118 mol) of n-butyllithium (1.6 molar in hexane) are added dropwise, under a nitrogen atmosphere, to a solution, cooled to -78° C., of 25 ml (0.157 mol) of 5-phenylpentyne in 400 ml of anhydrous diethyl ether. The whole is stirred at -78° C. for 15 minutes and then at 0° C. for 75 minutes. There is then added dropwise to that solution a solution, cooled to -78° C., of 6-methoxy-1-oxa-spiro[2.5]oct-5-en-4-one (11 g; 71.33 mmol) in 80 ml of anhydrous toluene. After 1 hour's stirring at -78° C., the reaction mixture is poured into an aqueous 10% ammonium chloride solution (1000 ml). Conventional treatment of the organic phase yields 22 g (74 mmol) of 4-hydroxy-6-methoxy-4-(5-phenylpenten-1-yl)-1-oxa-spiro[2.5]octene (2 isomers) in the form of an oily residue which is used in the following step without being purified. Hydrogenation of a solution of 22 g (74 mmol) of that mixture of isomers in 610 ml of benzene in the presence of 10 g of Lindlar catalyst for a period of 7 hours results, after filtration and evaporation, in 22 g (73 mmol) of 4-hydroxy-6methoxy-4-(5-phenylpentyl)-1-oxa-spiro[2.5]oct-5-ene in the form of an oily residue which is used in the following step without being purified.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:13]1([CH2:9][C:8]2[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-acetamidobenzaldehyde (200 mg), piperidine (0.121 mL), NaBH(OAc)3 (636 mg) and DIPEA (0.617 mL) in DCM (4 mL) was stirred at RT for 4 h. DCM and sat. NaHCO3 were added. The phases were separated, the org. layer was dried (Na2SO4), filtered off and evaporated to dryness to afford 267 mg of white solid. LC-MS (B): tR=0.45 min; [M+H]+: 233.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([O:31][CH2:32][CH2:33]O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:30][CH2:29][O:31][CH2:32][CH3:33])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: CCOCCO
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOCCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Yield: 75.7 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-hydroxyphenyl)methanone (0.39 g, 1.00 mmol) and ethylene glycol mono ethyl ether (2 mmol) were converted to 350 mg of the title compound by the procedure of Example 1 using 520 mg (2.0 mmol) of triphenylphosphine and 2.0 mmol of diethyl azodicarboxylate the only difference being that the total reaction time was 18 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(O)(C)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)c(-c2cccnc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(-c2cccnc2)c1)Oc1ccccc1
Temperature: -40 °C
Yield: 94.7 %

Procedure:
4-Chloro-3-(pyrid-3-yl)aniline (0.08 g, 0.00039 mole) in isopropyl alcohol (8 ml) was cooled to -40° C. and treated under argon with triethylamine (0.06 ml, 0.00043 mole) followed dropwise by phenyl chloroformate (0.051 ml, 0.00041 mole). The reaction mixture was stirred at -40° C. for half an hour and allowed to warm to ambient temperature. The solvent was removed in vacuo and the residue dissolved in dichloromethane, washed with HO, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.12 g, 95%) as an orange solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@H:18]2[C@H:22]([OH:23])[C@H:21]([OH:24])[C@@H:20]([CH2:25][O:26][CH3:27])[O:19]2)=[C:11]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[OH:23][C@@H:22]1[C@H:21]([OH:24])[C@@H:20]([CH2:25][O:26][CH3:27])[O:19][C@H:18]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:9]([CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[N:10][C:11]=2[NH:28][CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Methanesulfonyl chloride (27 mg, 0.22 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (120 mg, 0.23 mmol) (Example 11) and triethylamine (0.1 ml, 0.72 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 2 hr when the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (98:2) increasing in polarity to (95:5). This gave the title compound (87 mg) as a powder. MS: 583 (MH+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(OCC)(=O)C>[CH3:14][S:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:17])=[O:16]
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)(F)F
Reaction time: 1 h

Procedure:
To a mixture of 2,2,2-trifluoroethanol (5 g), triethylamine (14 ml) and ethyl acetate (120 ml) was added dropwise methanesulfonyl chloride (5.8 ml) with cooling it on ice, and stirred at this temperature for 1 hour. The reaction solution was filtered through a small amount of silica gel, followed by NH silica gel, which in turn was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to yield the title compound (9.5 g).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[Br:16][C:17]1[C:18](F)=[C:19]2[O:23][C:22]([CH:24]3[CH2:26][CH2:25]3)=[N:21][C:20]2=[C:27]([C:30]#[N:31])[C:28]=1[CH3:29]>CS(C)=O>[Br:16][C:17]1[C:18]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:19]2[O:23][C:22]([CH:24]3[CH2:25][CH2:26]3)=[N:21][C:20]2=[C:27]([C:30]#[N:31])[C:28]=1[CH3:29]
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Br)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Yield: 26.4 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (157 μl, 1.24 mmol) and triethylamine (348 μl, 2.50 mmol), were added to a dimethyl sulfoxide (5 ml) solution of 6-bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (304 mg, 1.03 mmol). The system was purged with nitrogen and then sealed up and heated at 90° C. for 2 hours. After cooling, the solvent was evaporated away under reduced pressure, then the resulting residue was dissolved in chloroform, washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, the resulting residue was washed with a mixed solvent of isopropyl ether and ethanol. The crystal was collected by filtration to obtain the entitled compound (106 mg, 26%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine (19.4 mg, 0.068 mmol) in 1 mL of DMF cooled at 0° C. was added methyl iodide (100 uL, 1.61 mmol), followed by sodium hydride (60% oil suspension, 5 mg, 0.13 mmol). The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched by adding 50 uL of water, diluted with 25 mL of ethyl acetate, washed with water (25 mL×3), saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography (20% ethyl acetate/hexanes) to give the title compound (14.3 mg, 0.048 mmol, 70%). 1H NMR (CDCl3) 8.06 (d, J=2.7 Hz, 1H), 7.57-7.79 (m, 1H), 7.60 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 7.44 (dd, J=8.7 and 2.7 Hz, 1H), 7.09 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 6.99-7.02 (m, 1H), 6.82 (dd, J=8.7 and 0.6 Hz, 1H), 3.97 (s, 3H), 3.61 (s, 3H).
Reaction SMILES: C1COCC1.[H-].[Na+].[C:8]([O:12][CH3:13])(=[O:11])[CH2:9][OH:10].[F:14][C:15]1[CH:20]=[C:19](F)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25]1[C:26](=[O:36])[N:27]([CH3:35])[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>O>[F:14][C:15]1[CH:20]=[C:19]([O:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25]1[C:26](=[O:36])[N:27]([CH3:35])[C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1
Reactant: COC(=O)CO
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1cc(F)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
To 20 ml of THF, 0.24 g (60 mmol) of 60% sodium hydride was suspended under cooling with ice, and 0.32 g (6.6 mmol) of methyl glycolate, was added thereto, followed by stirring for 15 minutes. To this mixture, 2 g (6.0 mmol) of 3-(2,4-difluoro-5-nitrophenyl)-1-methyl-6-trifluormethyl-2(1H)-pyridone was added, followed by stirring at room temperature for 3 hours. The product was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. After distilling off ethyl acetate under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 1.57 g (yield: 65%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[CH3:13][C:14]([CH3:26])([CH3:25])[C:15]#[C:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18].C(=O)(O)[O-].[Na+].[Cl-]>C(O)(C)C.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:16]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:15]([C:14]([CH3:26])([CH3:25])[CH3:13])[O:11][N:10]=1
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)C#CC(=O)c1cccnc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)(C)c1onc(-c2ccc(Cl)cc2Cl)c1C(=O)c1cccnc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 76.6 %

Procedure:
A mixture of 72 mg (0.32 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 60 mg (0.32 mmol) of 4,4-dimethyl-1-(3-pyridyl)-2-pentyn-1-one, and 32 mg (0.38 mmol, 1.2 equivalents) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. for 16 hrs on a rotary table shaker. A second addition of 25 mg of carboximidoyl chloride and 10 mg of sodium bicarbonate was followed by another 20 hrs at 55° C. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 92 mg of oily product, 3-(2,4-dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)carbonyl]isoxazole. 1H NMR (CDCl3): δ 1.47 (s, 9), 7.90 (m, 1), 7.60 (br s, 1) and 8.72 ppm (br s, 1). MS m/z: 375.0 (M+H).
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12](F)=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4].[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.CCOCC>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC/N=C/c1c(Cl)cccc1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
This compound was prepared using methodology described in Synthesis 1999, 2138-2144. To a solution of 21.2 g (99.2 mmol) butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine in 150 ml tetrahydrofuran at 0° C. was added dropwise 38.0 ml (114 mmol) of a 3 M solution of ethylmagnesium bromide in ether at such a rate that the temperature of the reaction mixture was maintained below 20° C. After the addition was complete, the reaction mixture was stirred for a further 1 h at room temperature. The reaction mixture was then quenched by dropwise addition of water and diluted with ethyl acetate. The mixture was washed sequentially with water and with saturated brine, then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was resuspended in carbon tetrachloride and concentrated in vacuo again to afford 19.7 g (89%) of the title compound as a yellow oil which was used in the next step without further purification. MS (ISP): 226.3 ([{37Cl}M+H]+), 224.3 ([{35Cl}M+H]+). 1H NMR and MS analysis indicated that this material contained ca 13% of the by-product butyl-[1-(2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine. MS (ISP): 208.3 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([CH:5]=[CH2:6])[C:3]#[N:4].[CH2:7]([O:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[N:22]1[S:26](=[O:28])(=[O:27])[NH:25][C:24](=[O:29])[CH2:23]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:7]([O:14][C:15]1[CH:20]=[C:19](/[CH:6]=[CH:5]/[CH:2]([CH3:1])[C:3]#[N:4])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][C:24](=[O:29])[NH:25][S:26]1(=[O:28])=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC(C)C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C#N)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 110 °C

Procedure:
A mixture of 2-methyl-but-3-enenitrile (18 mg, 0.225 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.113 mmol), Pd(OAc)2 (5 mg, 0.023 mmol) and triethylamine (11 mg, 0.107 mmol) in THF (3 mL) is placed in a microwave vial and heated at 110° C. for 10 min. The mixture is filtered and the filtrate concentrated. The residue is purified by reverse phase HPLC to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:17][CH:16]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2o1

Procedure:
A solution of 4-[2-(N-methyl-N-(2-benzoxazolyl)amino)ethoxy]benzaldehyde (1.6 g) and 2,4-thiazolidinedione (0.63 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered to give the title compound (mp 227°-9° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:32][C:31]4[CH2:30][CH2:29][NH:28][CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH:18]([C:33]([O:35]CC)=[O:34])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[ClH:2].[C:33]([CH:18]1[CH2:17][N:16]([S:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=3)[CH:9]=2)(=[O:15])=[O:14])[CH2:21][CH2:20][N:19]1[C:22]([C:24]1[S:32][C:31]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]=2[CH:25]=1)=[O:23])([OH:35])=[O:34]
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1cc2c(s1)CCNC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1cc2c(s1)CCNC2

Procedure:
In tetrahydrofuran (1 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (95 mg) was dissolved, followed by the addition of ethanol (2 ml) and 1N sodium hydroxide (3 ml). The resulting mixture was heated under reflux for 30 minutes. To the reaction mixture, 4N hydrochloric acid (2 ml) was added and the precipitate thus obtained was collected by filtration, whereby the title compound (83 mg, 90%) was obtained as a colorless foam.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][C:32]1([F:36])[CH2:35][NH:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:34]2[CH2:35][C:32]([F:36])([F:31])[CH2:33]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: FC1(F)CNC1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CC(F)(F)C2)c1OCCC(C)c1ccc(F)cc1
Yield: 37 %

Procedure:
Example 8a (102 mg, 0.21 mmol) was reacted with 3,3-difluoroazetidine hydrochloride (2.6 eq.) as described under General Procedure K and the crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 60:40) to afford the title compound as a pale yellow oil (39 mg, 37%). 1H NMR (300 MHz, CDCl3) δ7.20-7.17 (m, 2H), 7.01-6.95 (m, 2H), 3.98-3.91 (m, 4H), 3.83 (s, 3H), 3.62 (t, J=12.0 Hz, 4H), 2.99 (m, 1H), 2.80 (t, J=5.6 Hz, 2H), 2.50 (s, 3H), 2.18 (s, 3H), 2.07-2.01 (m, 2H), 1.30 (d J=6.9 Hz, 3H). MS (ES+) m/z 500.1 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH3:20][N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN1CCC[C@H]1CN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1CN1CCNCC1
Yield: 94.1 %

Procedure:
To a solution of (S)-1-benzyl-4-[(1-methylpyrrolidin-2-yl) methyl] piperazine 0.71 g (2.61 mmol) in 40 ml THF was added 10% Pd/C 0.4 g and exposed to 1 atm hydrogen overnight. The reaction mixture was filtered. The filtrate was concentrated to give 0.450 g of desired product in 94% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH2:15])=[N:11]1.C(N(CC)CC)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](Cl)=[O:27]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:26](=[O:27])[C:25]2[C:24]([F:23])=[CH:32][CH:31]=[CH:30][C:29]=2[F:33])=[N:11]1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2Cl)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
1-[(2,4-Dichlorophenyl)methyl]-1H-pyrazol-3-amine (40 μl, 0.23 mmol, Art-Chem GmbH) was dissolved in dichloromethane (2 ml). Triethylamine (64 μl, 0.46 mmol) and then 2,6-difluorobenzoyl chloride (49 mg, 0.28 mmol, Aldrich) were added and the reaction was stirred at room temperature for 2 h. The reaction was quenched by addition of water (5 ml). The organic phase was separated (by hydrophobic frit) and concentrated under a flow of nitrogen. The residue was purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid) (Method A). The appropriate fractions were concentrated in vacuo then under nitrogen flow. The sample was dissolved in methanol and applied to a 5 g aminopropyl ion exchange cartridge (prewashed with MeOH) and eluted with MeOH. The relevant fractions were combined and concentrated to give the title compound as a colourless solid (36 mg); LCMS: (System 1) MH+=382/384, tRET=3.47 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Yield: 99.2 %

Procedure:
2 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3[2-carboxyethynyl]-cyclopropane-carboxylate in 41 ml of ethyl acetate were hydrogenated in the presence of 0.38 g of 10% palladium hydroxide on barium sulfate and 0.4 ml of quinoline and the mixture was filtered. The filtrate was washed with 0.5N hydrochloric acid, then with water until neutral, dried and evaporated to dryness under reduced pressure to obtain 2 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3-[(Z)2-carboxyethenyl]-cyclopropane-carboxylate melting at 94° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=O)[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26][CH2:27][CH2:28]P(OCC)(OCC)=O)(=[O:25])[CH3:24].CN(C)C=O.[H-]>O>[CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:24]/[C:23]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Reactant: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a mixture of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (12.90 g), diethylphosphonoethyl acetate (9.60 ml) and N,N-dimethylformamide (200 ml) was added hydride (60% in oil, 1.94 g) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, washed successively with saturated brine, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration to give ethyl (E)-3-(1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)propenoate (14.50 g, yield 91%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 88–89° C.