Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[K+].[K+].[K+].FC(F)(F)[C:11]([OH:13])=[O:12].[CH3:16][C:17]#[N:18]>>[P:1]([O:5][CH2:16][C@@H:17]([C:11]([OH:13])=[O:12])[NH2:18])([OH:4])([OH:3])=[O:2]
Reactant: CC#N
Reactant: O=C(O)C(F)(F)F
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@@H](COP(=O)(O)O)C(=O)O
Reaction time: 2 h

Procedure:
In vitro Phosphorylation of Synapsin I by MAP Kinase and Identification of MAP Kinase-Dependent Phosphorylation Sites. Synapsin I was purified from rat and bovine brain as earlier described. MAP kinase, p44mpk, and the cyclin-dependent protein kinase (cdkl)-cyclin A complex were purified from sea star oocytes and assayed as earlier described by using 50 μM [γ-32P] ATP (DuPont/NEN) and 5 μM synapsin I. For stoichiometric phosphorylation, reactions were carried out for 2 hours with 7 μM synapsin I in the absence (MOCK-P) or presence of the indicted protein kinase. Samples were subjected to SDS/PAGE, followed by staining with Coomassie blue. Incorporation of 32P was quantitated by using a PhosphorImager (Molecular Dynamics). Two-dimensional phosphopeptide map analysis and phosphoamino acid analysis and in-gel MAP kinase assays were performed as earlier described. For sequence determination, rat synapsin I (340 μg) was stoichiometrically phosphorylated with p44mpk in the presence of trace amounts of [γ-32P]ATP and digested for 36 hours at 37° C. in a buffer containing 100 mM Tris (pH 8), 10% (vol/vol) CH3CN, 1% hydrogenated Triton X-100, and 17 μg each of trypsin and chymotrypsin; 1 M urea was added after 18 hours, 32P-labeled phosphopeptides were purified in a two-step procedure by reversed-phase HPLC using a C18 column (0.46×15 cm, Vydac, Hesperia, Calif.). Two major 32P-labeled peaks were isolated by linear gradient elution in the first chromatographic step [buffer 1:10 mM potassium phosphate [pH 2.2] with an increasing concentration of 40% CH3CN/20% isopropanol] Peaks 1 and 2 were further processed with a different buffer system (buffer 2:0.1% trifluoroacetic acid with increasing concentrations of 70% CH3CN). Peak 1 was resolved into two 32P-labeled phosphopeptides (peaks 1A and 1B), which appeared to be pure on the basis of absorbance profiles at 214 nm. Peak 2 was eluted as a single 32P-labeled peak in the second step. Each phosphopeptide was derivatized with ethanethiol prior to automated Edman degradation. The sequence obtained for peak 1A corresponded to residues 533-554 of rat synapsin I, with phosphoserine at residue 549: peak 1B corresponded to residues 54-76, with phosphoserine at residues 62 and 67; peak 2 corresponded to residues 54-73, with phosphoserine at residues 62 and 67.
Reaction SMILES: [N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[S:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH2:16][CH2:17][N:18]([C:28](=[O:30])[CH3:29])[CH2:19][CH:20]=3)[S:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(=O)Cl
Reactant: O=C(c1csc(C2=CCNCC2)c1)N1CCCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of azepan-1-yl-[5-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophen-3-yl]-methanone (0.023 g, 0.08 mmol) in DCM (1 mL) was added triethylamine (0.27 mmol) and acetyl chloride (0.11 mmol). The reaction mixture was stirred for 1 hour, and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.009 g). LCMS m/z 333.11 [M+H]+ RT=8.18 min (Analytical Method 2).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)cc1
Reaction time: 10 h

Procedure:
A mixture of 0.1 mol 4-fluorobenzaldehyde, 0.15 mol malonic acid, and 0.1 ml piperidine in 30 ml pyridine is boiled for 10 hours, cooled, and treated with 150 ml HCl having a 10% concentration. The precipitate is filtered and crystallized with ethanol. The yield of 4-fluorocinnamic acid is 68% and the melting point is 211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[N:7](C)[C:8](=O)C(F)(F)F.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[NH:7][CH3:8]
Reactant: CN(C(=O)C(F)(F)F)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
5-Chloro-N-methyl-2-nitro-N-trifluoroacetylaniline (30 g) from Example 9 was dissolved in methanol (300 ml), followed by addition of an aqueous 15% NaOH solution and subsequent addition of methanol (50 ml) under stirring for 3 hours. The reaction mixture solution was poured into water (400 ml), and the precipitate was given by filtration, which was then washed with water. The precipitate was dissolved in methylene chloride (300 ml), and then the methylene chloride layer was washed with water and saturated sodium chloride solution to dry the product over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the title compound was given (19 g; 96%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])[CH:12]=2)[CH2:17]1)=[O:29]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: O=C(O)Cc1ccccn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)Cc1ccccn1)C2
Reaction time: 8 h
Yield: 40.2 %

Procedure:
200 mg of N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 69 mg of 2-pyridineacetic acid, 111 mg HOBT, 276 mg EDC and 0.6 ml triethylamine are dissolved in 7 ml DMF and stirred overnight. The mixture is evaporated and the residue is treated with 5 ml water and 10 ml of dichloromethane. After separation, the water phase is washed with dichloromethane and the combined organic phases are filtered, dried and evaporated. 80 mg of a colorless oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][CH:9](Cl)[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][CH:9]([CH2:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Clc1ccc(CCC(Cl)Cn2ccnc2)s1
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(CCC(Cn2ccnc2)Sc2ccccc2Cl)s1

Procedure:
A mixture of 850 mg of 1-[4-(5-chloro-2-thienyl)-2-chloro-n-butyl]imidazole, 670 mg of 2-chlorothiophenol and 500 mg of potassium carbonate in 40 ml of acetone is stirred and refluxed for 4 hours. The solvent is evaporated under vacuum and 50 ml of water is added. The resulting mixture is extracted with ether and the ether extract is washed with water, dried and evaporated to afford 1-[2-(2-chlorophenylthio)-4-(5-chloro-2-thienyl)-n-butyl]imidazole as an oil. This material is converted to the nitrate salt by treatment with nitric acid, which salt is recrystallized from acetone/ethyl acetate as colorless flakes, mp 121°-122°.
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH3:22][C:23]12[CH2:29][C:28](=O)[CH:27]1[CH:26]=[CH:25][CH2:24]2>O>[CH3:22][C@:23]12[CH2:29][C:28](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:27]1[CH:26]=[CH:25][CH2:24]2
Reactant: CC12CC=CC1C(=O)C2
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C=C1C[C@]2(C)CC=C[C@@H]12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.29 g, 14.7 mmol) was added dropwise at 0° C. over 5 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.59 g, 63%, 15.5 mmol), and the mixture was stirred at 0° C. for 15 minutes. To this solution, a tetrahydrofuran (15 mL) solution of 1-methylbicyclo[3.2.0]hept-3-en-6-one (1.60 g, 13.1 mmol) was added dropwise at 0° C. over 10 minutes, and the mixture was stirred at room temperature for 4 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (1.80 g, 62%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18][CH2:19][CH2:20][NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]=[C:28]=[S:29]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:28]([NH:27][CH3:26])=[S:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN=C=S
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 36.1 %

Procedure:
There was dissolved 3.0 g (0.0082 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-aminoethylthio)acetamide in 50 ml of chloroform. Thereto was added dropwise a solution of 0.6 g (0.0082 mol) of methyl isothiocyanate in 10 ml of chloroform, and then the mixture was refluxed with heating for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 1.3 g of the titled compound as oily matter.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[N:13]=1.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[CH2:1]([S:8][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1cccc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(SCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Benzyl mercaptan (0.99 g, 7.94 mmol) and sodium hydride (60% in oil, 0.35 g, 8.66 mmol) were added to THF (30 ml), and the mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.22 mmol) in THF (10 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and brine. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.63 g, 100%) as a pale pink oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:10]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[Na])(C)=O.[OH2:47].O.O.[NH2:50]O.Cl.C(O)(=O)C>C1COCC1.CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:10]1=[N:50][OH:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1=O)OCC
Reactant: NO
Reactant: O
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1=NO)OCC
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of diethyl (((2 S,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-oxotetrahydro-2H-pyran-2-yl)methyl)phosphonate (1.3 g, 2.23 mmol, 1.0 equiv) in THF/MeOH (42 mL, 1:1) was treated with a buffer solution (17.68 mL) prepared with 15 g of AcONa.3H2O and 7.5 g of NH2OH.HCl. The pH was then adjusted to 4.5 by dropwise addition of acetic acid. After 1 hour, the mixture was extracted with DCM (3×30 mL), and the organic layer was washed sequentially with water (50 mL), saturated aqueous sodium bicarbonate solution (75 mL) and finally with water to neutrality. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product thus obtained was purified by silica gel chromatography, eluting with 60% EtOAc in hexane to give diethyl (((2S,4R,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-(hydroxyimino)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (0.98 g, 74%) as a mixture of E and Z isomers as a white solid. NMR data refers to the more abundant isomer. 1H NMR (400 MHz, DMSO-d6) δ 11.36 (d, J=1.1 Hz, 1H), 7.39-7.25 (m, 13H), 7.21 (dd, J=7.6, 2.0 Hz, 2H), 5.21 (td, J=10.6, 3.2 Hz, 1H), 4.73 (d, J=12.0 Hz, 1H), 4.64 (d, J=11.5 Hz, 1H), 4.57-4.47 (m, 4H), 4.40 (d, J=6.6 Hz, 1H), 4.04-3.91 (m, 5H), 3.71 (t, J=6.0 Hz, 1H), 3.60 (dd, J=10.1, 4.9 Hz, 1H), 3.53 (dd, J=10.2, 4.7 Hz, 1H), 2.70-2.53 (m, 1H), 2.11 (ddd, J=19.4, 15.7, 3.8 Hz, 1H), 1.19 (qd, J=7.1, 1.1 Hz, 6H). ESI (M+1) 598.0; calc for C32H40NO8P 597.3.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[N:6][C:7]1[CH:8]=[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].CS(N1C2C(=CC=C(N)C=2)[CH:26]=[CH:25]1)(=O)=O.[ClH:34].CCOCC>CO.C(O)(C)C>[ClH:34].[CH3:17][S:14]([N:13]1[C:9]2[C:10](=[CH:11][CH:12]=[C:7]([N:6]=[C:2]3[NH:3][CH2:4][CH2:5][NH:1]3)[CH:8]=2)[CH:26]=[CH:25]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Nc1cccc(N=C2NCCN2)c1
Reactant: CS(=O)(=O)n1ccc2ccc(N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: CC(C)O
Product: CS(=O)(=O)n1ccc2ccc(N=C3NCCN3)cc21

Procedure:
3.82 g of 2-chloroimidazoline hydrogen sulfate (see Example 6A) was treated with 50 ml of 1M NaOH solution and immediately extracted with CH2Cl2 (3×20 ml). The extracts were dried (K2CO3) and the solution decanted. 10 ml of isopropanol was added and the CH2Cl2 was removed at reduced pressure. The resultant isopropanol solution was added to a refluxing solution of the N-methanesulfonyl-6-aminoindole (2.02 g, 9.61 mmol) in isopropanol (10 mmol). The mixture was refluxed for 3 hr, cooled, and concentrated under vacuum. A portion (800 mg) of the crude product was dissolved in MeOH:H2O (5:1) then 10 g of silica gel was added. The mixture was dried under vacuum and the resulting powder was applied to a silica gel column and eluted with ethyl acetate:MeOH:iPrNH2 (93:5:2) (iPr=isopropyl). The white solid obtained was suspended in MeOH (4 ml) and treated with 3 ml of 1.0M HCl/ether. The solid dissolved then a precipitate formed which was filtered off after chilling the mixture in an ice bath. 590 mg of N-methanesulfonyl-6-(imidazolidin-2-ylideneamino)indole hydrochloride were obtained (mp 167.6-170.6° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:19]#N)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)=[O:22]>[Ni]>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=[O:22])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: O=CO
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#N)ccc21
Agent: [Ni]
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.0 g) and Raney nickel (3.0 g) were suspended in formic acid (10 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→20:80). The purified product was condensed under reduced pressure to give the title compound (0.92 g) as a yellowish-white solid (yield=92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7]=1[OH:8].[C:20](O)(=O)[CH:21]([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:7]3[O:8][C:20]([CH:21]([CH3:23])[CH3:22])=[N:1][C:2]=3[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=2)=[CH:14][CH:13]=1
Reactant: CC(C)C(=O)O
Reactant: COC(=O)c1cc(N)c(O)c(-c2ccc(F)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2oc(C(C)C)nc2c1
Temperature: 150 °C
Yield: 55 %

Procedure:
To a solution of methyl 5-amino-4′-fluoro-6-hydroxybiphenyl-3-carboxylate (10.0 mg, 38.0 μmol), and isobutyric acid (2.60 mg, 29.0 μmol), and solid support triphenylphosphine (75% by weight; 40.2 mg, 0.12 mmol) in acetonitrile (0.38 mL) was added trichloroacetonitrile (7.68 μL, 77.0 μmol). The mixture was heated in a microwave reactor for 15 min at 150° C. The mixture was cooled to ambient temperature, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (5 mg). LC-MS [M+1]=332.1.
Reaction SMILES: [Na].Cl[Sn:3](Cl)(Cl)[CH2:4][CH2:5][CH2:6][NH2:7].[CH:10]([OH:13])([CH3:12])[CH3:11]>>[CH3:11][CH:10]([CH3:12])[O-:13].[CH3:11][CH:10]([CH3:12])[O-:13].[CH3:11][CH:10]([CH3:12])[O-:13].[NH2:7][CH2:6][CH2:5][CH2:4][Sn+3:3]
Reactant: CC(C)O
Reactant: NCCC[Sn](Cl)(Cl)Cl
Agent: [Na]
Product: CC(C)[O-]
Product: NCCC[Sn+3]
Temperature: 70 °C
Yield: 59 %

Procedure:
0.57 g of sodium (0.025 mol) was treated with 80 ml of isopropylalcohol in a 200 ml eggplant type flask and the mixture was heated at 60° C. until sodium was completely dissolved. To this solution 50 ml of an isopropylalcohol solution containing the 3-(trichlorostannyl)propylamine (4.9 mmol), prepared in the aforementioned example (4), was added dropwise at a room temperature. Subsequently, the mixture was stirred while heating for 6 hours at 70° C. The resultant supernatant was separated and concentrated under reduced pressure to yield 2.4 g of the final product of 3-aminopropyltin tris(methylethoxide) (yield=59%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(5-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:14]=1[NH2:15]>>[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1c(F)cc(F)c(F)c1F
Product: O=C(O)Cc1ccccc1Nc1c(F)cc(F)c(F)c1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,3,4,6-tetrafluoroaniline to yield 2-[(2,3,4,6-tetrafluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]#[CH:9])[C:3]([NH:5][CH3:6])=[O:4].[CH2:10]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O1CCOCC1>[CH3:1][N:2]([CH2:7][C:8]#[C:9][CH2:10][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]([NH:5][CH3:6])=[O:4]
Reactant: C#CCN(C)C(=O)NC
Reactant: C=O
Reactant: C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)N(C)CC#CCN1CCCCC1

Procedure:
A solution of N,N'-dimethyl-N-(2-propynyl)urea (2.5 g, 0.02 mol) (Example A), paraformaldehyde (0.6 g, 0.02 mol), piperidine (1.7 g, 0.02 mol), and a spatula tip of cuprous chloride in 150 ml of anhydrous dioxane is allowed to reflux for two hours. After cooling the solution is made strongly acidic with a 2N solution of hydrochloric acid and washed with diethyl ether. The aqueous solution is then made basic by the addition of solid potassium carbonate until saturated, followed by extraction with diethyl ether (2X). The diethyl ether solution is dried over magnesium sulfate, filtered, and concentrated to afford a yellow oil. Nuclear Magnetic Resonance (NMR) (CDCl3): 4.81 (brs, 1H); 4.11 (t, J=1.9 Hz, 2H); 3.24 (t, J=1.9 Hz, 2H); 2.93 (s, 3H); 2.81 (d, J=4.4 Hz, 3H); 2.48 (m, 4H); 1.63 (m, 6H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.C(OCC)C>O1CCCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of cis-ethyl 2-aminocyclopentanecarboxylate (1.57 g, 10 mmol) in 50 mL tetrahydrofuran was added 4-chlorobenzenesulfonyl chloride (3.17 g, 15 mmol) and triethylamine (2.1 mL, 15 mmol). The reaction was stirred at room temperature for 4 h, then diluted into 100 mL diethyl ether and washed with 100 mL water. The organic layer was concentrated and purified by flash chromatography on a 120 g silica gel column with 10 to 40% ethyl acetate in hexane, 20 min gradient, to yield cis-ethyl 2-(4-chlorophenylsulfonamido)cyclopentanecarboxylate (3.05 g, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 7.76-7.80 (2H, m), 7.43-7.47 (2H, m), 5.57 (1 H, d, J=8.56 Hz), 3.91-4.10 (2H, m), 3.70-3.81 (1H, m), 2.74 (1H, dt, J=8.31, 6.55 Hz), 1.64-1.98 (5H, m), 1.44-1.58 (1H, m), 1.18 (3H, t, J=7.05 Hz). LC/MS R.T.=2.00 min; [M+H]+=332.07; [M+Na]+=354.04.