Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[C:13](Br)[C:14]=1[NH2:15])=[O:4].[C:17]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[C:13]([CH3:17])[C:14]=1[NH2:15])=[O:4]
Reactant: COC(=O)c1c(N)c(Br)cc2ncccc12
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c(N)c(C)cc2ncccc12
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
To 1.59 g (5.66 mmol) of 6-amino-7-bromo-quinoline-5-carboxylic acid methyl ester in 30 mL of dioxane under an atmosphere of argon is added 2.35 g (17.0 mmol) of K2CO3, 323 mg (0.28 mmol) of tetrakis(triphenylphsophine)palladium and 710 mg (5.66 mmol) of trimethylboroxine. The reaction mixture is stirred in a microwave oven at 180° C. for 10 minutes. After filtration over Celite and concentration in vacuo, the residue is purified by flash chromatography (SiO2, ethyl acetate) y to afford 550 mg of product (45%) as a yellowish solid; LC/MS:217/218 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:26][CH3:27])[CH2:21][N:20]([C:22](=O)[CH2:23][OH:24])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1)[CH3:2]>C1COCC1>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:26][CH3:27])[CH2:19][N:20]([CH2:22][CH2:23][OH:24])[CH2:21]4)[N:14]3[CH3:17])=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(=O)CO)C3)n(C)c2n1
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(CCO)C3)n(C)c2n1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 1-{3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-methoxyazetidin-1-yl}-2-hydroxyethanone (88 mg, 0.17 mmol) in THF (2 mL) at 0° C. was added BH3.THF complex (350 μL, 0.35 mmol, 1M solution) and the resulting mixture allowed to stir for 1 h. Further BH3.THF complex (800 μL, 0.80 mmol) was added and the mixture stirred at r.t. for 17 h. The reaction mixture was quenched with H2O, acidified with 2M HCl then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 849 as a white solid (74 mg, 86%). LCMS (method I): RT 2.48 min, [M+H]+ 493.4. 1H NMR (DMSO, 400 MHz): δ 8.04-8.04 (1 H, m), 7.64-7.63 (1 H, m), 7.27-7.23 (2 H, m), 4.50-4.42 (1 H, m), 4.39-4.14 (4 H, brd m), 4.05-3.98 (2 H, m), 3.80 (4 H, t, J=4.56 Hz), 3.70 (3 H, s), 3.52-3.45 (2 H, m), 3.40 (2 H, q, J=5.63 Hz), 3.34-3.24 (2 H, m), 3.01 (3 H, s), 2.65-2.57 (2 H, m), 1.34 (3 H, t, J=7.43 Hz)
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9]>C(OC(=O)CCC)(=O)CCC.CCCCCC>[C:2]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9])(=[O:6])[CH2:3][CH2:4][CH3:7]
Reactant: Cc1noc(N)c1C(N)=O
Agent: CCCC(=O)OC(=O)CCC
Solvent: CCCCCC
Product: CCCC(=O)Nc1onc(C)c1C(N)=O
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 173.6 %

Procedure:
A mixture of 5-amino-3-methyl-isoxazole-4-carboxylic acid amide (2 g, 14.18 mmol) in 10 ml of butyric anhydride was stirred at 150° C. for 0.5-1 h. The brown solution was diluted with hexane (100 ml) and cooled to room temperature. The solid crushed out from the mixture was filtered and washed with hexane, dried in vacuo. The title amide (2.6 g) was obtained as white solid.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][CH:7]([C:9]([F:12])([F:11])[F:10])[CH3:8])(=[O:3])[CH3:2].[OH-].[Na+]>O>[C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][CH:7]([C:9]([F:11])([F:12])[F:10])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CC(C)C(F)(F)F)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](CC(C)C(F)(F)F)C(=O)O
Reaction time: 0.38 h

Procedure:
To a suspension of N-acetyl-5,5,5-trifluoroleucine (4.2 g, 18.5 mmol) in H2O (35 mL) was added 1 M aqueous NaOH (18.5 mL, 18.5 mmol) and the mixture was stirred for 15 to 30 min to give a homogenous solution. Acylase I (EC 3.5.1.14, from Sigma, Cat. # A 3010; 55 mg) was added and the mixture was stirred at room temperature overnight. Crude NMR of a small aliquot (evaporated under vacuum) showed a ratio of 53:47 for starting material and product. The mixture was then acidified with 6M aqueous HCl (˜3.5 mL) and extracted with EtOAc (4×, each EtOAc extraction was washed with a small amount of H2O). The combined EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to afford the crude N-acetyl-5,5,5-trifluoro-D-leucine as a pale yellow solid, [α]D=+27.6° (c 1.5, EtOH). The aqueous layer was concentrated under vacuum and dried under vacuum overnight to afford 5,5,5-trifluoro-L-leucine, probably contaminated with NaCl and HCl salts, [α]D=−−4.1° (c 0.77, H2O).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([CH2:23]O)=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:25])[N:9]([CH3:26])[CH2:8]1)=[O:5])[CH3:2].CC(C)(C)C(Cl)=O.N.[Li].[Cl-].[NH4+]>N1C=CC=CC=1.C(Cl)(Cl)Cl.O>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([CH3:23])=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:25])[N:9]([CH3:26])[CH2:8]1)=[O:5])[CH3:28]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(CO)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Agent: CC(C)(C)C(=O)Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C

Procedure:
715 mg of 1,1-diethyl-3-(2,6-dimethyl-13-hydroxymethyl- 8alpha-ergolinyl)-urea (1.5 mmol) is dissolved in 10 ml of pyridine and mixed with 2 ml of trimethylacetyl chloride. Ice is added after 30 minutes of stirring at room temperature, it is stirred for another 30 minutes, made alkaline with ammonia and the mixture is cooled in an ice bath. The precipitated crystals are suctioned off, yield 785 mg, [α]D =-2° (0.5% in chloroform). The mother liquor is extracted with dichloromethane, dried and concentrated by evaporation. Both fractions are dissolved together in 6 ml of tetrahydrofuran and the solution is instilled in 50 ml of condensed, anhydrous ammonia. Then, it is mixed with 160 mg of lithium and the blue solution is stirred for 30 minutes at -40° C. Solid ammonium chloride, until decolorization, and 5 ml water are added in succession, the ammonia is evaporated and it is diluted with 80 ml of water. After 30 minutes of stirring in an ice bath, the precipitated crystals are suctioned off and dried in a vacuum, yield 643 mg (94% of theory), [α]D =+3° (0.5% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:22][CH2:21]2)[C:9](N2[C@@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:20]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][OH:10])[CH2:22][CH2:21]1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)C(c1ccc(Cl)cc1)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(c1ccc(Cl)cc1)C1CC1

Procedure:
This compound was prepared in a manner analogous to that of Step F, using 0.80 gram (0.0025 mole) of diastereomer (B) of (S)-N-[2-(4-chlorophenyl)-2-cyclopropylacetyl]-4-(1-methylethyl)-2-oxazolidinone (prepared in Example 3, Step E) and 0.30 gram (0.008 mole) of lithium aluminum hydride in 15 mL of tetrahydrofuran. The yield of stereoisomer (B) of 2-cyclopropyl-2-(4-chlorophenyl)ethanol was 0.45 gram as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[NH2:2]>C(OC(=O)C)(=O)C>[C:1]([C:4]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C(N)=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C#N)c1ccccc1
Yield: 32.9 %

Procedure:
A mixture of ethyl (RS)-4-(2-carbamoyl-5-benzyloxyphenoxy)-4-phenylbutanoate (1.9 g) and acetic anhydride (50 mL) is stirred at reflux for 2 hours. The reaction mixture is evaporated to low bulk and the residue is dissolved in ethyl acetate (50 mL). This solution is washed with aqueous sodium hydrogen carbonate and water, dried, and evaporated. Flash chromatography, eluting with a mixture of cyclohexane and dichloromethane (15:85 v/v), gives ethyl (RS)-4-(2-cyano-5-benzyloxyphenoxy)-4-phenylbutanoate (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)[CH:7]=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].N1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:7]=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18]
Reactant: COC(=O)c1cc(NC(=O)CCCCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCCC2=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
Subsequently, 5-(4-chloro-butyrylamino)-2-nitro-benzoic acid methyl ester (50 mg) was dissolved in N,N-dimethylformamide (5 ml). Morpholine (70 mg) and potassium carbonate (44 mg) were added to the solution at room temperature, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-nitro-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (45 mg, yield 100%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]([C:21]34[CH2:30][CH:25]5[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]5)[CH2:22]3)[CH2:28]4)=[O:20])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[N:11]1[C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[C:14]([NH:18][C:19]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:20])=[N:13][CH:12]=1
Reactant: O=C(Nc1ncnc2c1CCN(Cc1ccccc1)C2)C12CC3CC(CC(C3)C1)C2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ncnc2c1CCNC2)C12CC3CC(CC(C3)C1)C2

Procedure:
Adamantane-1-carboxylic acid (7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide (1.1 g, 2.64 mmole) was suspended in 30 ml of methanol. To the mixture was added palladium hydroxide on carbon (20% wt, 0.41 g) and the reaction was shaken under 60 PSI of hydrogen gas for 16 hrs. The mixture was filtered through celite and the filtrate was concentrated to give the desired product as an off white solid (0.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:8][C:7]1[C:2]2[N:1]=[C:20]([CH3:21])[C:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:24][CH:23]=3)=[C:17]([CH3:18])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: Nc1cc(O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 170 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (2.2 g), 3-(4-chlorobenzyl)pentane-2,4-dione (3.4 g) and toluene-4-sulfonic acid (few crystals) was heated at 170° C. under nitrogen for 10 hours. The mixture was cooled to room temperature and purification by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (1:19 by volume), followed by trituration with diethyl ether gave title compound as a pale brown solid, 0.41 g.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[C:22]([O:24]C)=[O:23])=[O:12])[S:2]1.CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[C:22]([OH:24])=[O:23])=[O:12])[S:2]1
Reactant: COC(=O)C1Cc2ccccc2N1C(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1Cc2ccccc2N1C(=O)NCCCCC1CCSS1
Yield: 50.9 %

Procedure:
The reaction was carried out as described in Example 48, but using 200 mg of methyl 1-[4-(1,2-dithiolan-3-yl)butylcarbamoyl]indoline-2-carboxylate (prepared as described in Example 93), 4 ml of methanol, 2 ml of tetrahydrofuran and 1.0 ml of a 1N 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 2N aqueous hydrochloride acid and 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 dissolved in dioxane and then lyophilised, to obtain 98 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.12 (silica gel thin layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]=[CH2:11])=[CH:4][CH:3]=1.[CH3:12][S:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH3:11])[C:14]([S:13][CH3:12])=[CH:15][N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: C=CNCc1ccc(Cl)nc1
Solvent: CCO
Product: CCN(Cc1ccc(Cl)nc1)C(=C[N+](=O)[O-])SC

Procedure:
A mixture of N-((6-chloropyridin-3-yl)methyl)ethenamine and 1,1-dimethylthio-2-nitroethene is dissolved in ethanol and refluxed for 4-8 hours. After completion, the mixture is concentrated and purified by column chromatography to obtain N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroethenamine.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=3)[CH:8]=2)[NH:3]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=3)=[CH:6][CH:5]=2)[C@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:11][C@@H:2]1[CH3:1])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)N[C@@H]1C[C@H](C)Nc2ccc(-c3cn(CC(=O)OC(C)(C)C)cn3)cc21
Product: CC(=O)N1c2ccc(-c3cn(CC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 78 %

Procedure:
A solution of 1,1-dimethylethyl {(cis)-4-[2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetate (for a preparation see Intermediate 88) (1.0 g, 2.33 mmol) in acetic anhydride (2 mL) was allowed to stand at room temperature for 16 h then most of the solvent was concentrated in vacuo. The residue was co-evaporated twice with toluene. Purification of the resulting residue by flash chromatography on silica gel (gradient: 0 to 2% MeOH in DCM) gave 1,1-dimethylethyl {(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetate (862 mg, 1.832 mmol, 78%) as a pale yellow solid.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4](=[O:10])[CH:5]=[C:6]([CH3:9])[NH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)=O.[F:20][C:21]([F:27])([F:26])[CH:22](OC)[OH:23]>O.C(O)(=O)C>[OH:2][C:3]1[C:4](=[O:10])[CH:5]=[C:6]([CH3:9])[NH:7][C:8]=1[CH:22]([OH:23])[C:21]([F:27])([F:26])[F:20]
Reactant: Cc1cc(=O)c(O)c[nH]1
Reactant: COC(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)c(O)c(C(O)C(F)(F)F)[nH]1
Temperature: 100 °C

Procedure:
5-Hydroxy-2-methyl-1H-pyridin-4-one hydrochloride (1.00 g, 6.19 mmol) and potassium carbonate (1.02 g, 7.42 mmol) was mixed together in water (10 mL) at room temperature, and stirred until evolution of carbon dioxide ceased. Then, 2,2,2-trifluoro-1-methoxy-ethanol (1.60 g, 12.4 mmol) was added. The reaction mixture was heated in a sealed flask at 100° C. for 20 h. The mixture was cooled down to RT and neutralized with acetic acid to pH at between 5 to 6. The precipitate was collected by suction filtration and washed with water and ether. Thus, 3-hydroxy-6-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one was obtained as an off-white solid (1.06 g, 76% yield). 1H NMR (90 MHz, DMSO-d6) δ (ppm): 6.09 (s, 1H, CH); 5.42 (apparent q, 1H, CH), 2.28 (s, 3H, CH3); MS-ESI (m/z) 224.1 [M+1]+, 206.1, 186.1, 178.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][C:15]#[CH:16]>CC(C)=O>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:15]#[CH:14]
Reactant: C1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
Prepared using methodology as described in US 2005/0026944. To a stirred mixture of piperidine (851 mg, 10.0 mmol), cesium carbonate (3.26 g, 10.0 mmol) and acetone (20 mL) was added 3-bromoprop-1-yne (1.49 g, 10.0 mmol; 80% in toluene) at room temperature. The white suspension was stirred for 18 hours at room temperature. The suspension was filtered, and the filtrate was concentrated. The resulting residue was triturated with diethyl ether (10 mL), filtered, and the filtrate concentrated to obtain the product as an oil (0.70 g, 56%). 1H NMR (400 MHz, CDCl3) δ 3.27 (d, J=2 Hz, 2H), 2.50 (m, 4H), 2.22 (t, J=2 Hz, 1H), 1.62 (m, J=6 Hz, 4H), 1.43 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH3:25])[CH2:18][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)CCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(O)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 60.7 %

Procedure:
Diphenylmethylpiperazine (2.20 g) was dissolved in dimethylformamide (25 ml), and then 1-chloro-3-pentanol (1.78 g) and potassium carbonate (722 mg) were added thereto, followed by stirring the mixture at 80° C. for 15 hours. After evaporation of dimethylformamide, water was added to the residue and the resultant was extracted 3 times with ethyl acetate. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.79 g of amorphous 1-(4-(diphenylmethyl)piperazinyl)pentane-3-ol. Yield: 61%.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[C:5](#[N:8])[CH2:6][CH3:7]>>[NH2:8][C:5]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH2:6][CH3:7]
Reactant: OP(O)O
Reactant: CCC#N
Product: CCC(N)(P(=O)(O)O)P(=O)(O)O
Reaction time: 10 h
Yield: 71 %

Procedure:
Into a reactor like the above was charged 261 g phosphorous acid. 44.3 g propionitrile was introduced slowly for 70 minutes at 135°-143° C. into the agitated phosphorous acid. The reactant mixture was held for additional 10 hours at 150°-155° C. The 1-aminopropane-1, 1-diphosphonic acid produced was isolated from the reaction mixture in the manner described in Example 1.
Reaction SMILES: [CH2:1]([C:5]1[CH:22]=[CH:21][C:8]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:7]([F:23])[CH:6]=1)[CH2:2][CH2:3][CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:36][O:37][CH2:38][CH2:39][OH:40]>>[CH2:1]([C:5]1[CH:22]=[CH:21][C:8]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([NH:36][O:37][CH2:38][CH2:39][OH:40])=[O:14])=[C:7]([F:23])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NOCCO
Reactant: CCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 68 %

Procedure:
The title compound was prepared from reaction of 2-(4-butyl-2-fluoroanilino)-3,4-difluorobenzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica (50% EtOAc/Hexane as eluant) to give 2-(4-butyl-2-fluoroanilino)-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a white solid (68%); m.p. (EtOAc/Hexane) 163-165° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.74 (br s, 1 H), 7.44-7.38 (m, 1 H), 7.14-7.06 (m, 1 H), 7.06-7.01 (m, 1 H), 6.88 (dd, J=8.3, 1.1 Hz, 1 H), 6.83 (ddd, J=8.4, 8.4, 4.2 Hz, 1 H), 4.73 (br s, 1 H), 3.87 (t, J=4.8 Hz, 2 H), 3.58 (t, J=4.8 Hz, 2 H), 2.52 (t, J=7.5 Hz, 2 H), 1.57-1.48 (m, 2 H), 1.29 (sextet, J=7.3 Hz, 2 H), 0.89 (t, J=7.3 Hz, 3 H). Anal. Calcd for C17H15F3N2O3: C, 59.7; H, 5.5; N, 7.3. Found C, 59.4; H, 5.4; N, 7.4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1.[CH3:19][C:20]1([CH3:29])[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22](=O)[CH2:21]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:13]1([C:11](=[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21]2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccccc1)c1ccc(OCCO)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(OCCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a stirred suspension of Zn (0.65 g, 9.91 mmol) in THF (10 mL) was added TiCl4 (0.55 mL, 4.95 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. After cooling to room temperature, a solution of 5 (0.30 g, 1.24 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.59 g, 3.71 mmol) in THF (17 mL) was added at once. The reaction mixture was refluxed for another 2.5 h. Following cooling to room temperature, the reaction was quenched with 10% K2CO3 (40 mL). The quenched reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated to give a pale yellow oil. The residue was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc:hexanes to give 6 as a white solid (0.35 g, 78%). mp 131-132° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.95 (s, 2H), 1.99 (s, 2H), 3.80-3.85 (m, 2H), 4.00-4.05 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 7.10-7.20 (m, 3H), 7.20-7.25 (m, 2H). LRMS (ESI): m/z 365 (M+H)+. Anal. Calcd for C25H32O2: C, 82.37; H, 8.85. Found: C, 82.11; H, 9.03.