Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH:25]=[C:26](Br)Br)[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.[CH2:32]([Sn](CCCC)(CCCC)CCCC)[CH:33]=C.COC1C=CC(P(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([C:25]#[C:26][CH:32]=[CH2:33])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1O[C@@H](Cn2cc(C=C(Br)Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Agent: [Pd]
Agent: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC#Cc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 80 °C
Yield: 13.9 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 25) (0.3 g, 0.52 mmol), allyl tributyl tin (160 μl, 0.55 mmol) and tris(4-methoxyphenyl)phosphine (28 mg, 0.08 mmol) were dissolved in DMF (2.5 ml). Diisopropylethyl amine (136 μl, 0.78 mmol) was added, the reaction mixture was flushed with argon and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) was added. The mixture was heated to 80° C. for 10 hours under argon. It was diluted with ethyl acetate, washed with phosphate buffer (pH 7), saturated aqueous potassium fluoride solution and with water and dried over sodium sulfate. Chromatography on silica gel with chloroform/methanol (15:1) gave 32 mg (14%) of the title compound as a colourless solid.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)[CH:2]=[CH2:3].C(=O)(OCC=C)O[CH2:17][CH:18]=[CH2:19]>Cl[Pd]Cl>[CH2:19]([N:8]1[C:7]([CH3:14])([CH3:13])[CH2:6][CH:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH2:10][C:9]1([CH3:12])[CH3:11])[CH:18]=[CH2:17]
Reactant: C=CCOC(=O)OCC=C
Reactant: C=CCOC1CC(C)(C)NC(C)(C)C1
Agent: Cl[Pd]Cl
Product: C=CCOC1CC(C)(C)N(CC=C)C(C)(C)C1
Temperature: 110 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
4-allyloxy-2,2,6,6-tetramethyl-piperidine (150 g, 0.76 mol), di-allyl carbonate (115 g, 0.8 mol) and PdCl2 (1.35 g, 1.6 mmol) are charged under nitrogen atmosphere into a 3-necked 500 ml-flask equipped with a thermometer and a reflux condenser. The solution is heated under stirring to 110° C. for 24 hours. Gas-chromatographic analysis of the reaction mixture then shows that the reaction produced the desired 1-allyl-4-allyloxy-2,2,6,6-tetramethyl-piperidine in 63% yield (calculated on the starting 4-allyloxy-2,2,6,6-tetramethyl-piperidine) and >97% selectivity.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][C:7]=1[C:13]1[C:19]([OH:20])=[C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([C:28]([CH3:36])([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]=1[OH:15])([CH3:5])[CH3:4])#[N:2].C([OH:46])C.[OH-].[Na+]>Cl>[NH2:2][C:1]([C:3]([C:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][C:7]=1[C:13]1[C:19]([OH:20])=[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:17]([C:28]([CH3:35])([CH3:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]=1[OH:15])([CH3:4])[CH3:5])=[O:46]
Reactant: CCCCCCC(C)(C)c1c(Cc2ccccc2)c(O)c(C2=C(C(C)(C)C#N)CCC(C)C2)c(O)c1Cc1ccccc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCC(C)(C)c1c(Cc2ccccc2)c(O)c(C2=C(C(C)(C)C(N)=O)CCC(C)C2)c(O)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
A solution of 2.0 g. of 2-[2-(1-cyano-1-methylethyl)-5-methyl-1-cyclohexenyl]-5-(1,1-dimethylheptyl)-dibenzylresorcinol in 6 ml. of ethanol containing 10 ml. of fifty percent aqueous sodium hydroxide solution was heated at reflux and stirred for 32 hours. After cooling the reaction mixture to room temperature, the excess reaction solvent was removed by evaporation under reduced pressure to provide a residue which was next dissolved in aqueous hydrochloric acid. The product was extracted from the aqueous acid solution into diethyl ether. The ethereal extracts were combined, washed with water, and dried. Removal of the solvent affered 2.0 g. of 2-[2-(1-aminocarbonyl-1-methylethyl)-5-methyl-1-cyclohexenyl]-5-(1,1-dimethylheptyl)dibenzylresorcinol as a solid. M.P. 113°-114° C. M+ 595.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:21])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[S:2]1.[OH-].[Na+]>CO>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:21])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:2]1
Reactant: COC(=O)CCCCNC(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCNC(=O)NCCCCC1CCSS1
Yield: 80 %

Procedure:
The reaction was carried out as described in Example 48, but using 0.30 g of methyl 5-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}pentanoate (prepared as described in Example 119), 10 ml of methanol and 3.14 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 0.23 g of the title compound as pale yellow crystals, melting at 125 to 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1.[Br-].C(N[C@H]1CCCC[C@@H]1NCC1C=CC=CC=1)C1C=CC=CC=1.C(N[C@H]1CCCC[C@@H]1NCC1C=CC=CC=1)C1C=CC=CC=1.[Ni+2].[Br-]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C@@H:6]([CH:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH2:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Agent: [Ni+2]
Agent: [Br-]
Agent: c1ccc(CN[C@H]2CCCC[C@@H]2NCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
This hydrated coarse crystal of 4-chloro-β-nitrostyrene was dissolved in toluene (19 ml), the aqueous phase was separated by a liquid-separation operation, and the organic phase was azeotropically dehydrated under reduced pressure, to distill off 9.5 ml. A catalyst prepared according to a method described in non-patent document 2 (nickel(II)bis[(S,S)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide) (58 mg, 0.072 mmol) and dimethyl malonate (2.3 g, 17 mmol) were added, and the mixture was heated up to 50° C. and stirred at the same temperature for 7 hours. After completion of the reaction, the reaction solution was washed with 0.1 mol/L hydrochloric acid (5 ml) and water (5 ml) each once. The organic phase was concentrated under reduced pressure, and crystallized in a toluene/heptane solvent, to obtain 4.2 g (13 mmol) of a title compound. Yield 75%. The spectrum data corresponded to the value in non-patent document 3. The optical purity of the resultant title compound was measured by HPLC to find a value of 94% ee.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[NH2:11])=[O:5])[CH3:2].[H-].[Na+].[CH3:14][C:15]([CH3:25])=[CH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.[BH4-].[Na+]>CN(C=O)C.CCOC(C)=O.CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]2[C:15]([CH3:25])([CH3:14])[CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:11][C:7]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1N
Reactant: CC(C)=CC(=O)c1ccccc1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn2c1NC(c1ccccc1)CC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
Compound 1 (0.68 g, 4.41 mmol) was dissolved in DMF (5 mL). NaH (60% in mineral oil, 0.19 g, 4.7 mmol) was added at room temperature affording rapid gas evolution. The reaction stirred for 0.5 h upon which 3-methyl-1-phenyl-but-2-en-1-one (0.50 g, 3.15 mmol) was added. The reaction stirred for 0.5 h upon which EtOH (5 mL) and NaBH4 (1.19 g) were added. The solution was brought to 60° C. for 0.5 h. and then cooled to room temperature. The solution was quenched with water, extracted with Et2O (3 times), dried (Na2SO4) and concentrated. Flash chromatography (10% AcOEt) to give the desired product as a tan solid (0.60 g, 63% yield). MS Calcd.: 298. Found 299 (M+H).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][Si](C)(C)C)=[CH:5][CH:4]=1.O>C(O)C.Cl>[CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)Oc1ccc([Si](C)(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)c1ccc(O)cc1
Reaction time: 0.08 h
Yield: 93.4 %

Procedure:
28.7 g p-trimethylsilylphenoxytrimethylsilane was dissolved in 9 ml 95 percent ethyl alcohol. One drop of concentrated hydrochloric acid and 4 ml water were added, and the mixture was shaked for 5 minutes. After standing for another 15 minutes, the mixture was washed two times with 30 ml water and separated. The organic phase was poured into a crystallizing dish; p-trimethylsilylphenol crystallized out as white needles. After drying overnight in vacuo, 18.7 g of product was obtained (mp 76 degrees Celsius).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:4].[OH-].[Na+].O>CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Yield: 77.9 %

Procedure:
1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione (1.6 g, 5.2 mmol), NaOH (0.31 g, 7.7 mmol), water (40 mL) and methanol (40 mL) were added into a 250 mL three-mouth flask. The mixture was refluxed and reacted for 3 hours. The methanol was removed via evaporation under reduced pressure after the reaction was finished. The mixture was adjusted to pH=2-3 by 3N HCl, forming many precipitates. The mixture was filtered and the solid was washed by water and methonal. The solids were dried to give the title compound as white solid (1.2 g, 78% yield). 1H NMR (300 M, DMSO-d6): 13.09 (brs, 1H), 11.77 (s, 1H), 8.01 (dd, J=7.7 and 1.4 Hz, 1H), 7.84-7.80 (m, 2H), 7.66-7.61 (m, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.27-7.21 (m, 2H), 5.36 (s, 2H). MS: m/z 297.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:19])([C:13]1[N:17]([CH3:18])[N:16]=[CH:15][N:14]=1)[CH2:3][CH2:4][P:5](=[O:12])([O:9]CC)[O:6]CC.C[Si](Br)(C)C.CO.C1OC1C>C(Cl)Cl.C(OCC)C>[OH:1][C:2]([CH3:19])([C:13]1[N:17]([CH3:18])[N:16]=[CH:15][N:14]=1)[CH2:3][CH2:4][P:5](=[O:6])([OH:12])[OH:9]
Reactant: CCOP(=O)(CCC(C)(O)c1ncnn1C)OCC
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cn1ncnc1C(C)(O)CCP(=O)(O)O
Reaction time: 16 h

Procedure:
To a solution of diethyl 3-hydroxy-3-methyl-3-(1-methyl-1,2,4-triazol-5-yl)propylphosphonate (1.2 g, 4.12 mmol) in CH2Cl2 (24 ml) was added TMSBr (2.72 ml, 20.6 mmol, 5 eq) at room temperature under nitrogen. The reaction mixture was stirred for 16 hours. Then methanol (12 ml) was added to the mixture. After stirring for 2 hours, addition of propylene oxide (2.4 ml) and dilution with diethylether gave colourless precipitates which were collected on a glass filter under nitrogen, washed with diethylether, and dried in vacuo to give pure 3-hydroxy-3-methyl-3-(1-methyl-1,2,4-triazol-5-yl)propyl-phosphonic acid, compound no 5.001 (0,63 g, 65% yield). ##STR49##
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C@@H:14]1[CH2:19][NH:18][CH2:17][C@H:16]([N:20]2[CH:28]=[N:27][C:26]3[C:25](=[O:29])[NH:24][C:23]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:22][C:21]2=3)[O:15]1.C(N(CC)CC)C.[C:48](Cl)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl>[OH:12][CH2:13][C@@H:14]1[CH2:19][N:18]([C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:17][C@H:16]([N:20]2[CH:28]=[N:27][C:26]3[C:25](=[O:29])[NH:24][C:23]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:22][C:21]2=3)[O:15]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2CNC[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Yield: 82 %

Procedure:
In 30 mL of dichloromethane was suspended 2.0 g of N9-{(2R,6S)-6-(hydroxymethyl)morpholin-2-yl}-N2-(phenoxyacetyl)guanine p-toluenesulfonate (REFERENCE EXAMPLE 1), and 13.9 g of triethylamine and 18.3 g of trityl chloride were added to the suspension under ice cooling. The mixture was stirred at room temperature for an hour. The reaction solution was washed with saturated sodium bicarbonate aqueous solution and then with, water, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. To the residue was added 40 mL of 0.2 M sodium citrate buffer (pH 3)/methanol (1:4 (v/v)), and the mixture was stirred. Subsequently, 40 mL of water was added and the suspension mixture was stirred for an hour under ice cooling. The precipitates were taken out by filtration, washed with cold methanol and dried to give 1.84 g of the objective compound (yield: 82.0%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[F:6][C:7]([F:15])([F:14])[C:8]1([C:11](O)=[O:12])[CH2:10][CH2:9]1.C(Cl)CCl.O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[CH3:5][O:4][N:3]([CH3:2])[C:11]([C:8]1([C:7]([F:15])([F:14])[F:6])[CH2:10][CH2:9]1)=[O:12]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CNOC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (7.17 g, 73.5 mmol) was added to an ambient temperature solution of 1-trifluoromethylcyclopropane-1-carboxylic acid (10.3 g, 66.8 mmol), EDC (15.4 g, 80.2 mmol), hydroxybenzotriazole hydrate (12.28 g, 80.2 mmol) and N-methylmorpholine (36.7 mL, 33.8 mmol) in methylene chloride (50 mL) at ambient temperature. After stirring at ambient temperature overnight, the reaction mixture was poured into ethyl acetate and washed successively with 2 M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated to afford N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide which was used in the subsequent step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:12]1[N:13]=[CH:14][C:9]([CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: Clc1ccc(CBr)cn1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21 %

Procedure:
Morpholine (7.0 g, 8.8 mmol) was added to the solution of 5-bromomethyl-2-chloro-pyridine in carbon tetrachloride (20 mL) and stirred at room temperature for 6 h. Water was added to the reaction mixture and the separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. Purification by column chromatography using silica gel (60-120 mesh) and ethyl acetate as eluent afforded 4-(6-chloro-pyridin-3-yl-methyl)-morpholine (1.2 g, 21%) as a brown oily liquid.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccc(CCCN)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
With 6.88 g (17.5 mmols) of t-butyl 3-[4-(3-phthalimidopropyl)phenyl]propionate were admixed 1.10 ml (22.8 mmols) of hydrazine hydrate and 50 ml of methanol. The mixture was refluxed for 1 hour, cooled to room temperature and then concentrated. The concentrate was dissolved in 200 ml of 1 mol dm-3NaOH, followed by extraction with ether. The extract was dried over K2CO3 and concentrated to give 4.14 g (yield 90%) of t-butyl 3-[4-(3-aminopropyl)phenyl]propionate in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[S:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[NH:4][C@H:3]1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:8]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C@H:5]1[N:4]([C:14](=[O:15])[CH3:3])[C@@H:3]([C:14]([OH:16])=[O:15])[C:2]([CH3:17])([CH3:1])[S:6]1)(=[O:13])[CH3:7]
Reactant: CC1(C)SC(c2ccccc2O)N[C@H]1C(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccccc1[C@@H]1SC(C)(C)[C@H](C(=O)O)N1C(C)=O
Reaction time: 20 h

Procedure:
A solution containing 1.0 g of 5,5-dimethyl-2-(2-hydroxyphenyl)-thiazolidine-4(S)-carboxylic acid in 7 ml of pyridine and 3 ml of acetic anhydride is kept for 20 hours, then the mixture is evaporated and three times 20 ml of toluene each are distilled from the residue. The remained crystalline material is recrystallized from the mixture of acetone and petroleum ether to give the title compound in a yield of 0.9 g (67.5 %), m.p.: 214°-216° C. [α]D22 =+34 (c=0.47, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1cccc(CCl)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cccc(F)c3)c2c1

Procedure:
The titled compound (47 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 3-fluorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CSC1C=CC=CC=1OC1C=CC=CC=1N>>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[F:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccccc1OCc1ccccc1
Agent: CSc1ccccc1Oc1ccccc1N
Product: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F

Procedure:
Using Procedure S-3 (Table 5) with 3-fluoroisonicotinic acid and 2-(benzyloxy)aniline the title compound 96 was obtained (4.01 g, 88%) as a white solid. MS (m/z): 323.2 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[O:14][C:11]2=[N:12][CH:13]=1.B([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:30]([OH:32])=[O:31])(O)O>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:35]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=1[C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[O:14][C:11]2=[N:12][CH:13]=1
Reactant: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Reactant: O=C(O)c1ccc(Cl)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Temperature: 180 °C
Yield: 46.8 %

Procedure:
Cesium carbonate (167 mg, 0.514 mmol) was added to Pd(Ph3P)4 (40 mg, 0.034 mmol), 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (100 mg, 0.342 mmol), 3-borono-4-chlorobenzoic acid (103 mg, 0.514 mmol) in DMF (3 mL) and Water (0.3 mL) at room temperature. The mixture was degassed 3× and the reaction was heated to 180° C. in the microwave for 10 min. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was triturated with MeOH to give the expected product 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (59 mg, 0.160 mmol, 47% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.22 (1H, br. s.), 8.36 (1H, d, J=2.26 Hz), 8.25 (1H, d, J=2.26 Hz), 8.03-8.11 (2H, m), 7.97-8.02 (2H, m), 7.77 (1H, d, J=7.78 Hz), 7.55 (1H, s), 7.41 (2H, t, J=8.78 Hz). LC-MS retention time: 1.15 min; m/z (MH+): 368. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.