Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][C:10]1[CH:11]=[C:12]2[N:17]([C:18]=1[C:19]([C:21]1[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:24]3=[O:36])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13]2.O>CN(C=O)C>[CH3:9][C:10]1[CH:11]=[C:12]2[N:17]([C:18]=1[C:19]([C:21]1[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:1])[CH:26]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:24]3=[O:36])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2ccc(C(=O)c3c(C)cc4ccccn34)cc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cn(C)c2ccc(C(=O)c3c(C)cc4ccccn34)cc2c1=O
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 87.5 %

Procedure:
1.53 g (11.12 mmol) of potassium carbonate and 0.69 ml (11.12 mmol) of methyl iodide are added, at ambient temperature under an inter atmosphere, to 3.73 g (9.27 mmol) of ethyl 6-[(2-methylindolizin-3-yl)carbonyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate in 100 ml of DMF. The reaction medium is heated at 90° C. for 2 h. 0.384 g (2.78 mmol) of potassium carbonate and 0.173 ml (2.78 mmol) of methyl iodide are added and then the heating is continued for 40 minutes. The reaction medium is hydrolysed with water and then extracted with ethyl acetate and with dichloromethane. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 3.15 g of a yellow solid are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:38]=[CH:39][CH:40]=1)[O:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:28]=1[Cl:37])[CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[C:42]1[N:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C(N(CC)CC)C>C(O)C>[ClH:37].[Cl:37][C:28]1[C:29]([C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:11]([CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: Clc1ncccn1
Reactant: NCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cl
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(CCNc3ncccn3)c2)CC(c2ccccc2)c2ccccc2)c1Cl

Procedure:
To a stirring solution of {3-[3-(2-amino-ethyl)-phenoxy]-propyl}-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine (57 mg, 0.1 mml, Example 150) and 2-Chloro-pyrimidine (97 mg, 0.85 mmol) in ethanol (10 mL) was added triethylamine (0.5 ml, 3.75 mmol). The resulting solution was refluxed for 72 hours and then concentrated in vacuo. Purification by preparative HPLC (YMC 75×30 mm, 25 m/min, 95-100% CH3CN) afforded the desired pyrimidine product. The free base was treated with 1 M HCl in Et2O (0.1 ml) and the mixture was concentrated in vacuo to afford the title compound as a solid, 44 mg (64%). MS(ES) m/e 645.4 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[CH:8][CH:7]=1.[S:31]1[CH:35]=[C:34]([CH:36]=O)[N:33]=[CH:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[C:23]2[CH2:28][CH2:27][N:26]([CH2:36][C:34]3[N:33]=[CH:32][S:31][CH:35]=3)[CH2:25][CH2:24]2)=[CH:10][CH:11]=1
Reactant: O=Cc1cscn1
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(Cc3cscn3)CC2)c2cccc3cccnc23)cc1
Reaction time: 20 h
Yield: 48.6 %

Procedure:
Compound 1C (3.3 g, 8.3 mmol) and 4-thiazolecarboxaldehyde (1.4 g, 12.4 mmol) in dichloroethane (16 mL) were stirred for 30 min. under nitrogen. Sodium triacetoxyborohydride (5.3 g, 24 9 mmol) was added and the reaction was stirred for 20 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated. Column chromatography (120 g silica gel, eluting with 4% 7N NH3/MeOH in CH2Cl2) gave 2.01 g 1D as a white solid (49%). 1H NMR (500.333 MHz, CDCl3) δ 8.90 (dd, J=4.1, 1.7 Hz, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (dd, J=7.3, 2.3 Hz, 1H), 7.51-7.46 (m, 2H), 7.37-7.33 (m, 3H), 7.31-7.29 (m, 2H), 7.18 (s, 1H), 3.85 (s, br, 2H), 3.76 (s, 2H), 3.67 (br s, 2H), 3.26 (br s, 1H), 3.02 (s, 3H), 2.78-2.71 (m, 1H), 2.67-2.52 (m, 4H), 2.46-2.37 (m, 1H), 2.14-2.04 (m, 2H). TOF MS E+ 499.21.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]#[C:22][C:23]1[CH:28]=[CH:27]C=CC=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(C1CC1)#C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]#[C:22][CH:23]1[CH2:27][CH2:28]1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2nc(C#Cc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: C#CC1CC1
Product: Cc1cc2nc(C#CC3CC3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropylethynyl)-7-methylquinolin-6-yl)acetic acid (38) (5.5 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)acetic acid of Example 37 except using ethynylcyclopropane instead of ethynylbenzene. 1H-NMR 400 MHz (CD3OD) 8.0 (m, 1 H), 7.84 (s, 1 H), 7.64-7.55 (4 H, m), 7.35 (d, J=7.6 Hz, 1H), 5.21 (s, 1 H), 2.72 (s, 3 H), 1.65 (m, 1 H), 1.13-1.02 (m, 4 H), 0.98 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C27H27ClNO3: 448.2. Found: 448.2.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (500 mg, 1.57 mmol) in DMF (11 mL) is added TEA (0.23 mL, 1.65 mmol) and ethyl 2-chloro-2-oxoacetate (0.18 mL, 1.57 mmol) at room temperature. After stirring for 1 hour at room temperature, the reaction is quenched with H2O, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=70:30 to 50:50) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-ethoxy-2-oxoacetamido)butanoate (550 mg). HPLC retention time=1.88 minutes (condition A); MS (m+1)=418.3
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH2:18][OH:19])[N:17]=[C:4]2[CH:3]=1.[CH3:20][S:21]([NH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:22]>>[OH:19][CH2:18][C:16]1[N:17]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[C:25]([NH:24][S:21]([CH3:20])(=[O:22])=[O:23])[CH:26]=[CH:27][CH:28]=3)[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]2[CH:15]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(CO)cn23)n[nH]1
Product: Cc1cc(Nc2nc(-c3cccc(NS(C)(=O)=O)c3)cc3nc(CO)cn23)n[nH]1

Procedure:
The title compound was synthesized using (7-chloro-5-(5-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-c]pyrimidin-2-yl)methanol and 3-(methylsulfonamido)phenyl boronic acid using the procedure described in Example 278. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 3.06 (s, 3H) 4.70 (s, 2H) 6.75 (s, 1H) 7.31 (dd, J=7.96, 1.64 Hz, 1H) 7.50-7.61 (m, 2H) 7.89 (d, J=8.08 Hz, 1H) 8.15 (s, 1H) 8.57 (s, 1H) 10.02 (s, 1H) 10.97 (s, 1H) 12.37 (s, 1H); ESI-MS: m/z calc'd for C18H19N7O3S 413.45; found 414.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13]C1CCCCO1)([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)COCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of 36.21 g of 2-[4-(2-tetrahydropyranyloxy)butyloxy]acetic acid tert-butyl ester in 360 ml of methanol, 47.77 g of p-toluenesulfonic acid monohydrate was added. After stirring at room temperature for 30 minutes, the reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution and the solvent was evaporated under reduced pressure. The residue was diluted with water, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 17.02 g of the desired compound as a colorless oily substance.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[Cl:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:9]1[CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1ccc(F)cc1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless crystalline powder.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8](I)=[C:7]([O:13][CH2:14][CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][O-].[Na+].[CH3:19][O:20][CH:21]=[O:22]>O1CCOCC1>[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:21]([O:20][CH2:19][CH3:16])=[O:22])=[C:7]([O:13][CH2:14][CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1I
Reactant: C[O-]
Reactant: COC=O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Cl)c(C(C)(C)C)cc1OCC
Temperature: 60 °C
Yield: 76.3 %

Procedure:
To a degassed solution of 4-tert-butyl-5-chloro-2-ethoxy-1-iodobenzene (2.2 g, 6.4 mmol), sodium methoxide (0.52 g, 9.6 mmol) and dichlorobistriphenylphosphinepalladium (0.25 g, 0.4 mmol) in dioxane (20 mL) was added methylformate (1.2 mL, 19.4 mmol). The resulting mixture was heated in an oil bath (60° C.) for 18 h and then allowed to cool. The solution was diluted with dioxane and filtered through a plug of Celite and concentrated. Purification of the crude residue by flash chromatography over silica gel using 5-20% ethyl acetate in hexanes gave ethyl 4-tert-butyl-5-chloro-2-ethoxybenzoate (1.39 g, 80%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.[BH4-].[Na+]>CO.C(OCC)C>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(C=O)c(F)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COc1cc(CO)c(F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-Bromo-2-fluoro-5-methoxy-benzaldehyde (4.03 g, 17.33 mmol) from step (1) below in Methanol at 0° C. was added NaBH4 (0.65 g, 17.33 mmol). After the reaction mixture was stirred at 0° C. for 2 hours, it was allowed to warm to room temperature. The organic layer was taken up in ethyl ether, washed with water and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (25-45% EtOAc in hexanes) to give the product. Yield: 3.90 g, 99.0%. 1H NMR (CDCl3) δ: 3.90 (s, 3H), 4.74 (d, J=6.02 Hz, 2H), 6.82 (d, J=6.1 Hz, 1H), 7.29 (d, J=10.58 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=2/[CH:17]=[CH:18]/[CH2:19][OH:20])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:33])[C:24]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])[C:24](=[O:25])[C:26]1[CH:27]=[CH:28][C:29]([O:20][CH2:19]/[CH:18]=[CH:17]/[C:9]2[C:10]([CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:30][CH:31]=1
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1/C=C/CO
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2c(-c3ccc(F)cc3)cccc2C(C)C)cc1
Yield: 59.3 %

Procedure:
As in Example 15, (E)-3-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yl]-2-propen-1-ol (0.58 g) was reacted with 4-hydroxyphenylglyoxylic acid methyl ester (0.387 g) in the presence of diethyl azoclicarboxylate (0.448 g) and triphenylphosphine (0.68 g) in tetrahydrofuran (25 mL). The usual work up afforded 1.3 g of a crude mixture that was purified by flash chromatography over silica gel (130 g; ethyl acetate-hexane; 3:7) to furnish 0.55 g of (E)-4-[3-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid methyl ester as a oil.
Reaction SMILES: [CH3:1][O:2][P:3]([S:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11])([O:5][CH3:6])=[S:4].[CH:20]1([O:51]P(O)(O)=O)[CH:25]([O:26][P:27]([OH:30])([OH:29])=[O:28])[CH:24]([O:31]P(O)(O)=O)[CH:23]([O:36]P(O)(O)=O)[CH:22]([O:41]P(O)(O)=O)[CH:21]1[O:46]P(O)(O)=O>>[CH3:6][O:5][P:3]([S:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11])([O:2][CH3:1])=[S:4].[C@@H:25]1([OH:26])[C@@H:24]([OH:31])[C@H:23]([OH:36])[C@@H:22]([OH:41])[C@@H:21]([OH:46])[C@H:20]1[OH:51].[P:27]([O-:30])([O-:29])([O-:28])=[O:26]
Reactant: O=P(O)(O)OC1C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C1OP(=O)(O)O
Agent: COP(=S)(OC)SCN1C(=O)c2ccccc2C1=O
Product: O=P([O-])([O-])[O-]
Product: O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
In another embodiment, the invention provides a method for hydrolyzing phospho-mono-ester bonds in phytate. The method includes administering (e.g., to an individual, e.g., a human, or an animal) an effective amount of a phytase of the invention (e.g., a phytase having a sequence identity of at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97.5%, 98%, 98.5%, 99%, 99.5%, or more, or complete (100%) sequence identity (i.e., homology) to SEQ ID NO:2 (a phytase polypeptide); SEQ ID NO:10 (a phytase polypeptide); a polypeptide having sequence as set forth in SEQ ID NO:8 and having at least one, or all, of the amino acid modifications W68E, Q84W, A95P, K97C, S168E, R181Y, N226C, Y277D, wherein the polypeptide has phytase activity) or other phytases, for example, the E. coli appA “wild type” phytase-encoding SEQ ID NO:7, or, a polypeptide sequence of SEQ ID NO:2 or the E. coli appA “wild type” phytase SEQ ID NO:8, to yield inositol and free phosphate. An “effective” amount refers to the amount of enzyme which is required to hydrolyze at least 50% of the phospho-mono-ester bonds, as compared to phytate not contacted with the enzyme.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH2:13][CH2:12][C@H:11]2[C:6](=CC[C@H]3[C@@](C(O)=O)(C)CCC[C@@]32C)[CH:5]=1)C.C(=S)([O-])N.[C:27]([O:31][CH2:32][CH2:33][OH:34])(=[O:30])[CH:28]=[CH2:29]>[O-]O>[CH2:1]=[CH:2][CH:4]=[CH2:5].[CH2:1]=[CH:2][C:4]1[CH:13]=[CH:12][CH:11]=[CH:6][CH:5]=1.[C:27]([O:31][CH2:32][CH2:33][OH:34])(=[O:30])[CH:28]=[CH2:29]
Reactant: CC(C)C1=CC2=CC[C@@H]3[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1
Agent: C=CC(=O)OCCO
Agent: NC([O-])=S
Agent: [O-]O
Product: C=CC=C
Product: C=Cc1ccccc1
Reaction time: 6.5 h

Procedure:
A butadiene-styrene-hydroxyethyl acrylate polymer was prepared by conventional free radical emulsion polymerization techniques using a mixed fatty acid -- rosin acid soap, a ferrous-formaldehyde-sulfoxalate activator, an organic hydroperoxide catalyst and a thiocarbamate shortstop. The polymerization temperature was 5° C. One part by weight of hydroxyethyl acrylate was present initially, a further one part was added at 20% conversion and a further one part was added at 40% conversion. The polymerization was stopped at 62% conversion after 6.5 hours polymerization time. The recovered polymer contained about 2.9 weight percent of hydroxyethyl acrylate and had a Mooney (ML-4 at 100 C) of about 60.
Reaction SMILES: C(N(C1C=CC([C:14]2[N:15]=[C:16]3[N:20]([CH:21]=2)[CH2:19][CH2:18][S:17]3)=CC=1)C(=O)C)CC.ClC(OCC)=O.C1C2C(CCCC2)CCC1.[S].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[N:39]1[CH:44]=[CH:43][C:42]([C:21]2[N:20]3[C:16]([S:17][CH2:18][CH2:19]3)=[N:15][CH:14]=2)=[CH:41][CH:40]=1
Reactant: CCCN(C(C)=O)c1ccc(-c2cn3c(n2)SCC3)cc1
Reactant: c1ccncc1
Agent: CCOC(=O)Cl
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Solvent: ClCCl
Product: c1cc(-c2cnc3n2CCS3)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The N-propylacetamido Formula (III) compound (0.60 g, 0.002 mole), prepared as described above in part a, was then suspended in CH2Cl2 (10 ml) and dry pyridine (0.47 ml, 0.006 mole) was added. The suspension was heated to aid in dissolving the solid, then cooled to ice-bath temperature. Ethyl chloroformate (0.72 ml, 0.648 g, 0.006 mole) in 2 ml CH2Cl2 was added dropwise to this mixture over a one hour period. The solution was stirred at room temperature for one hour and then heated at reflux for 10 min. The reaction was then cooled to 10° C. and an additional equivalent of pyridine (161 μl) and ethyl chloroformate (240 μl) was added. After heating at reflux for 10 min., the reaction was left to stir at room temperature overnight. The reaction was then washed with water (3×100 ml) and the organic layer stripped then decalin (5 ml) and sulfur (0.063 g, 0.002 mole) were added and the mixture was heated to 170° C. This temperature was maintained for one hour. The reaction was then diluted with CH2Cl2 and extracted with a 12% HCl solution. The acidic layer was basified with solid K2CO3 and then extracted with CH2Cl2. After treating with brine and MgSO4, the CH2Cl2 was removed, and the residue was flash chromatographed (0.10% MeOH/100-90% CH2Cl2) to give 0.2 g of a (Formula (I) compound), 6-4-(N-propylacetamido)phenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole (TLC: Rf =0.22 5% MeOH/95% CH2Cl2.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][CH3:45])[N:39]=2)=[CH:34][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:24].O>ClCCl>[CH2:23]([O:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]([CH3:45])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[N:39]=2)=[CH:34][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:24]
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(NC)n2)cc1)C(=O)OC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.8 %

Procedure:
0.96 g (4.8 mmol) of 4-nitrophenyl chloroformate and then 0.85 ml (4.8 mmol) of diisopropylethylamine are added to a solution of 1 g (3.2 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminopyrid-2-yl)phenyl]propanoate in 25 ml of dichloromethane. The reaction medium is stirred at room temperature for 1 hour 30 minutes. After addition of water and extraction with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and evaporated. 1.9 g (100%) of methyl 2(S) -ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)propanoate are obtained.
Reaction SMILES: [OH:1]O.N1(CCCC2N=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)CCOCC1.[C:26](O)([C:28](F)(F)F)=[O:27].N>C(Cl)Cl>[N+:14]([C:15]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][CH2:22]2)=[CH:18][C:16]=1[NH:17][C:26](=[O:27])[CH3:28])([O-:25])=[O:1]
Reactant: OO
Reactant: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 2.8 mL, ca. 56 mmol) was added dropwise to a stirred solution of TFM (7.9 mL, 56 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. The solution was added to a solution of 1-oxide 76 (1.76 g, 5.6 mmol) and TFA (2.2 mL, 28 mmol) in DCM (40 mL) at 0° C. and the solution was stirred at 20° C. for 6 h. Dilute aqueous NH3 solution (40 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 76 (173 mg, 10%); and (ii) 1,4-dioxide 77 (868 mg, 47%) as a yellow solid: mp (MeOH/DCM) 109-110° C.; 1H NMR δ 8.30 (s, 1H, H-9), 8.27 (s, 1H, H-5), 3.44 (br t, J=4.4 Hz, 4H, 2×CH2O), 3.24 (br t, J=7.3 Hz, 2H, CH2), 3.13-3.19 (m, 4H, H-6, H-8), 2.50 (t, J=6.5 Hz, 2H, CH2N), 2.38 (br t, J=4.3 Hz, 4H, 2×CH2N), 2.27 (p, J=7.5 Hz, 2H, H-7), 2.06-2.12 (m, 2H, CH2); 13C NMR δ 155.2, 155.1, 150.5, 139.0, 133.7, 115.8, 113.8, 67.0 (2), 58.0, 53.5 (2), 33.3, 32.8, 28.5, 25.5, 21.8. Anal. calcd for C17H22N4O3: C, 61.8; H, 6.7; N, 17.0. Found: C, 62.0; H, 6.8; N, 17.2%.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:9]1=2.O.N>ClCCl>[O:8]1[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9]1=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3ccoc23)CC1
Agent: N
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCNCC2)c2occc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Trifluoroacetic acid (5 ml) was added dropwise at 20° C. under nitrogen to a cooled solution of tert-butyl 4-(7-benzo[b]furanyl)piperazine-1-carboxylate (1.66 g) in dichloromethane (5 ml). The solution was stirred at ambient temperature for 1 hour, then poured into cold water (50 ml). The mixture was basified by the addition of aqueous ammonia solution, then the product was extracted into dichloromethane (2×50 ml). The combined organic extracts were washed with brine (100 ml), dried (MgSO4), and the solvent removed in vacuo to give 1-(7-benzo[b]furanyl)piperazine (1.02 g).