Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[C:19](O)=[O:20])=[O:5])[CH3:2].O>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:17])([CH3:16])[CH3:18])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Temperature: 0 °C
Yield: 73.2 %

Procedure:
To a cold (ice bath) solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclopentane-1,2-dicarboxylic acid monoethyl ester (epimeric mixture, 0.7 g) in tetrahydrofuran (3.5 mL) was slowly added a borane complex with tetrahydrofuran (1M, 2.7 mL). The resulting solution was stirred for 3 h in the ice bath then slowly poured into water. The mixture was extracted with diethylether. The combined organic layers were washed with brine and dried over sodium sulfate then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with cyclohexane/ethylacetate (6:1 v/v) as eluant to afford the title compound (0.49 g, 73%) as light yellow oil. MS (EI): 303.2 (M+H)+.
Reaction SMILES: C(=O)(O[C@H:4]1[C:17]2[CH:16]=[C:15]3[C:10]([N:11]([CH3:27])[C:12](=[O:26])[CH:13](CCC4C=CC=CC=4)[O:14]3)=[C:9](C(C)(C)C)[C:8]=2[O:7][C:6]([CH3:33])([CH3:32])[C@@H:5]1[OH:34])N.C(=O)([O-])O.[Na+].CCO[CH2:44][CH3:45]>Cl.O1CCOCC1>[OH:34][C@@H:5]1[C@@H:4]([NH:11][CH2:10][CH2:9][C:45]2[CH:44]=[CH:6][CH:5]=[CH:4][CH:17]=2)[C:17]2[CH:16]=[C:15]3[C:10]([N:11]([CH3:27])[C:12](=[O:26])[CH2:13][O:14]3)=[CH:9][C:8]=2[O:7][C:6]1([CH3:32])[CH3:33]
Reactant: CCOCC
Reactant: CN1C(=O)C(CCc2ccccc2)Oc2cc3c(c(C(C)(C)C)c21)OC(C)(C)[C@H](O)[C@H]3OC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1C(=O)COc2cc3c(cc21)OC(C)(C)[C@H](O)[C@H]3NCCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of t-butyl(2-phenylethyl)(7R*,8S*)-[7-hydroxy-4,6,6-trimethyl-3-oxo-4,6,7,8-tetrahydro-1,5-dioxa-4-aza-anthracene-8-yl] carbamate (115 mg, 0.24 mmol) in ether (2.2 mL), 4 mol/L hydrogen chloride-dioxane (500 μL) was added at room temperature, and the resulting mixture was stirred at room temperature for 5 hours and then at 50° C. for 30 minutes. Upon the completion of the reaction, saturated aqueous sodium hydrogencarbonate solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/2) and the aimed product was obtained (yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH2:31]Br)=[CH:24][CH:23]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[CH:28]([C:25]2[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=2)[C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[CH2:10][CH2:9]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CBr)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CN2CCN(c3ccccc3Cl)CC2)cc1
Yield: 14.6 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 1.5 g of 1-(2-chlorophenyl)piperazine and 5 ml of triethylamine, and 3.4 g of 2-[bis(4-hydroxyphenyl)methyl]benzylbromide was added thereto. The mixture was heated under reflux for 3.5 hours, and then insoluble substances were filtered off. The filtrate was concentrated, and the residue was subjected to extraction with the addition of water and ethyl acetate. The organic layer was separated, and the aqueous layer was then extracted with ethyl acetate. The organic layers were combined and then dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel chromatography to afford 0.54 g of the desired compound (Compound 89).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:18](Cl)[CH:19]=[CH2:20].[I-].[K+]>O1CCCC1>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:19]=[CH2:18]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=CCCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(=O)c2ccccc2)cc1

Procedure:
4-Hydroxybenzophenone (100 parts) was dissolved in tetrahydrofuran (100 parts). Potassium hydroxide (30.9 parts) was added, heated and stirred until completely dissolved. Allyl chloride (46.4 parts) and potassium iodide (42 parts) were added to this solution. The mixture was refluxed for 8 hours. After cooling, it was washed with water and the solvent removed by distillation. A crude product of the desired 4-allyloxybenzophenone was obtained. It was recrystallized in n-hexane to obtain 110 parts of 4-allyloxybenzophenone (melting point 71° C.) at 72% yield.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][C:13]([OH:15])=O.[C:18]([CH:21]1[CH2:26][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:24][CH2:23][NH:22]1)(=[O:20])[NH2:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:11][C:10]1[C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:16])=[C:6]([CH2:12][C:13]([N:22]2[CH2:23][CH2:24][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[CH2:26][CH:21]2[C:18](=[O:20])[NH2:19])=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1cccc(Cl)c1OCC(F)(F)F
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(C(=O)Cc2cccc(Cl)c2OCC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-3-chlorophenylacetic acid (0.14 g, 0.53 mmol) from Step 4 above, 2-carbamoyl-4-(2-methylphenyl)piperazine (0.12 g, 0.53 mmol) from Step 4 of Example 1, and HOBT (0.08 g, 0.53 mmol) in DMF (5 mL) was added EDC (0.15 g, 0.8 mmol) and DIEA (0.14 mL, 0.8 mmol). The mixture was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a H2O:CH3CN gradient containing 0.1% TFA. The product-containing fractions were lyophilized to give the title compound as an amorphous powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([N:17]([CH:24]2[CH2:29][CH2:28][C:27]([N:36]([CH3:38])[CH3:37])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)C(=O)C(F)(F)F)[C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:2]1.Cl>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:17][CH:24]2[CH2:29][CH2:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([N:36]([CH3:38])[CH3:37])[CH2:26][CH2:25]2)[C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(N(C(=O)C(F)(F)F)C(Cc2c[nH]c3ccccc23)c2nnn[nH]2)CC1
Agent: Cl
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(NC(Cc2c[nH]c3ccccc23)c2nnn[nH]2)CC1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
A suspension of N-(2-(1H-indol-3-yl)-1-(1H-tetrazol-5-yl)ethyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-2,2,2-trifluoroacetamide (100 mg, 0.19 mmol) in methanol (10 mL) was mixed with 37% hydrochloric acid (3 mL) and stirred for 7 h at 100° C. in a Teflon pressure vessel. 37% hydrochloric acid (3 mL) was then added again, the mixture stirred for a further 24 h at 100° C. and then concentrated to low volume in a vacuum. The raw product was purified by flash chromatography (85 g, 20×3.6 cm) with dichloromethane/methanol [2:1+1% NH3 (32% in H2O)].
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:5][O:6][C:7]1[C:8]([CH2:9][Cl:3])=[CH:11][CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)cccc1Oc1ccccc1C
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1c(CCl)cccc1Oc1ccccc1C

Procedure:
Thionyl chloride (30 ml) and pyridine (1 drop) were added to a solution of 2-methoxy-3-(o-tolyloxy)benzyl alcohol (44.0 g) in benzene (150 ml). The mixture was refluxed under heating for 40 minutes and then evaporated. The residue was dissolved in diethyl ether, washed with aqueous sodium bicarbonate and water successively, dried over magnesium sulfate and then evaporated to give oily o-tolyl 2-methoxy-3-chloromethylphenyl ether (47.50 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(=O)(O)[O-].[Na+].[Cl:28][CH2:29]OS(Cl)(=O)=O>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:28][CH2:29][O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[CH2:13][C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Reactant: O=S(=O)(Cl)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(OCCl)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Reaction time: 5 h

Procedure:
A solution of 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid in a 5% sodium bicarbonate solution is added to a solution of 1.5 equivalent of chloromethylchlorosulfate in methylene chloride. Tetrabutylammonium hydrogensulfate (catalytic amount) is added, and the mixture stirred vigorously for 5 hours. The organic layer is dried over MgSO4 and conc. in vacuo to give 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid chloromethyl ester as white solid.
Reaction SMILES: I[CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1>C(O)C.[Pd]>[CH3:2][C@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: C[C@@H]1CO[C@H](CI)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccccc2)[C@H](C)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of (2S,5R)-2-(iodomethyl)-5-methyl-4-(phenylmethyl)morpholine (5.0 g, 15.10 mmol) in ethanol (120 mL) stirred under nitrogen at room temperature was added Pd/C (1.607 g, 1.510 mmol) in ethanol (120 mL). The reaction mixture was purged with hydrogen, and was stirred under hydrogen at 25° C. for 2 hours. After the completion (by LCMS), the mixture was filtered through a pad of celite, the filtrate was purified by silica gel chromatography (300-400 mesh), eluting with petroleum/EtOAc (1:1) to afford the desired title compound (2.5 g) as a white solid. LC-MS (ES) m/z=206 [M+H]+. 1H NMR (CDCl3): δ 7.96-7.93 (m, 2H), 7.49-7.46 (m, 3H), 4.69-4.61 (m, 2H), 4.41-4.37 (m, 1H), 4.03-3.97 (m, 1H), 3.73-3.70 (d, J=12.8 Hz, 1H), 3.48-3.46 (d, J=6.4 Hz, 1H), 3.27-3.24 (d, J=12.4 Hz, 2H), 2.78-2.69 (m, 1H), 1.39-1.37 (d, J=6.4 Hz, 3H), 1.24-1.23 (d, J=12.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[O:25]>CCOCC.CCCCCC.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[F:8])[OH:25]
Reactant: Fc1ccccc1F
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1cccc(F)c1F
Temperature: -10 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of 5.6 g of 1,2-difluorobenzene in 50 ml of ether is cooled to −10° C, 31 ml of a 1.6 M solution of n-butyllithium in hexane are added drop wise and the mixture is stirred at −10° C. for 2 hours. The reaction mixture is cooled to −50° C., a solution of 4 g of 5-chloro-1H-indole-2,3-dione in 40 ml of THF is added and the resulting mixture is stirred for 12 hours, while allowing the temperature to return to RT. The reaction mixture is poured into a concentrated HCl/ice/water mixture, the resulting mixture is extracted with EtOAc, the organic phase is washed with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 2.8 g of the expected product are obtained after crystallization from iso-ether; m.p.=248° C.
Reaction SMILES: [CH3:1][C:2]1([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(S(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(S(C)(=O)=O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-methyl-4-methylsulfonyl-piperidine-1-carboxylate (430 mg, 1.550 mmol) in DCM (10 mL) was added TFA (3 mL, 38.94 mmol) and the solution stirred at room temperature for 1 h. The reaction was concentrated and azeotroped twice with DCM to give 4-methyl-4-(methylsulfonyl)piperidine as a sticky oil that was used in next step without further purification. MS (ES+) 178.0.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[NH2:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]2[N:25]([CH2:47][C:48](OCC)=[O:49])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][S:35]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=4[Cl:45])(=[O:37])=[O:36])=[C:30]([F:46])[CH:29]=3)[C:20]=12>COCCOC>[OH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@H:2]([N:11]([CH3:12])[C:48](=[O:49])[CH2:47][N:25]1[C:21]2=[N:22][CH:23]=[N:24][C:19]([NH2:18])=[C:20]2[C:27]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=3[Cl:45])(=[O:37])=[O:36])=[C:30]([F:46])[CH:29]=2)=[N:26]1)[CH3:1]
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Agent: [Li]CCCC
Solvent: COCCOC
Product: C[C@H]([C@@H](O)c1ccccc1)N(C)C(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 20.3 %

Procedure:
A solution of (+)-pseudoephedrine (0.037 g, 0.224 mmol) in ethylene glycol dimethyl ether (0.75 mL) was treated with a solution of n-butyllithium (2.5 M in hexanes, 0.060 mL, 0.150 mmol). After 20 min, this solution was transferred via cannula into a solution of ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.040 g, 0.074 mmol) in N,N-dimethylfortnamide (0.75 mL). The resulting solution was stirred at 50° C. for 15 h. It was then cooled to ambient temperature and partitioned between methanol/dichloromethane (1:9, 50 mL), and water (15 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 11.88-12.65 min) afforded N1-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N1-methyl-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white solid (0.010 g, 0.015 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 9.63 min; MS: (MH)+ 658.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])=[CH:5][CH:4]=1.[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:22][O:21][C:19]([N:10]1[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][CH:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:8][CH:7]=1)=[O:20]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)cc1
Yield: 99.3 %

Procedure:
Dimethyl 2-(4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (5.996 g, 17.36 mmol) was dissolved in acetonitrile (60 mL) and water (1.200 mL), then lithium bromide (12.06 g, 138.91 mmol) was added. Triethylamine (9.63 mL, 69.46 mmol) was added and the resulting brown suspension was heated under reflux for 1 h. Water and MTBE were added. The organic phase was extracted with water (×2). The combined aqueous layer was acidified to pH 1 with 3.8 M aq HCl and then extracted with MTBE (×2). The combined organic layer was washed with water and evaporated. Trace of water was azeotropically removed by MeCN. 1-(Methoxycarbonyl)-2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (5.71 g, 99%) was isolated as a brown oil. MS m/z 332 (M+H)+
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1](=[N:17][OH:18])([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1nccc(OCC(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1nccc(OCC(F)(F)F)n1
Yield: 69.7 %

Procedure:
2-Acetyl-4-(2,2,2-trifluoroethoxy)-pyrimidine (0.47 g) was dissolved in a mixture of ethanol (10 ml) and water (5 ml) and heated to 40° C. for 1 hour with hydroxylamine hydrochloride (0.16 g) and sodium acetate (0.43 g). The reaction mixture was poured into water and extracted with ethyl acetate (3×50 ml). The combined extracts were dried and concentrated. The residue was washed with hexane to give 2-acetyl-4-(2,2,2-trifluoroethoxy)-pyrimidine oxime (0.35 g, 70% yield) as a white solid, m.p. 179°-181° C.; 1H NMR (270 MHz): δ2.39(3H,s), 4.87(2H,q), 6.88(1H,d), 8.60(1H,d) ppm.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH3:36])[CH3:35])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH3:35])[CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (90 mg) is dissolved in ethanol (2 ml), and thereto is added a 2N-aqueous sodium hydroxide solution (207 μl), and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:4) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (29 mg). The resulting carboxylic acid is dissolved in ethanol (0.5 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (23 μl) and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid ethyl ester sodium salt (30 mg). MS (m/z): 623 [M−Na]−
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:16])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14]Cl)[N:13]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[C:2]([O:6][C:7](=[O:16])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][O:27][CH2:26][CH2:25][O:24][CH3:23])[N:13]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: COCCOCc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of the chloride (Intermediate II, 420 mg, 1.69 mmol) and potassium carbonate (818 mg, 5.92 mmol) in 2-methoxyethanol (12 ml) was stirred for 2 hours at 90° C. TLC indicated complete conversion. The mixture was filtered through a pad of celite and the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel, ethyl acetate/heptane, 25-70% gradient) to give 46% (225 mg, 781 μmol) of title compound as pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9H), 3.39 (s, 3H), 3.54-3.58 (m, 2H), 3.64-3.69 (m, 2H), 4.58 (s, 2H), 6.82 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].Cl[CH2:14][C:15](=[O:19])[C:16]([OH:18])=[O:17].ClCC(=O)C>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:14][C:15](=[O:19])[C:16]([OH:18])=[O:17]
Reactant: O=C(O)C(=O)CCl
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: CC(=O)CCl
Product: O=C(O)C(=O)COc1c([N+](=O)[O-])ccc(F)c1F

Procedure:
3.9 g of 2,3-difluoro-6-nitrophenol and 3.0 g of chloropyruvic acid are reacted as described for chloroacetone in Example 8 of U.S. Pat. No. 4,382,892, to yield (2,3-difluoro-6-nitrophenoxy)-pyruvic acid. Catalytic hydrogenation (Pd/C or Raney Ni, room temperature) of the product yields in one step 7,8-difluoro-[1,4]benzoxazine-3-carboxylic acid, which is converted to its acid chloride and then is reacted first with triethylphosphite and next with diethylphosphite and a base, to form 7,8-difluoro-3-[hydroxy-bis(diethoxyphosphono)methyl]-[1,4]benzoxazine. Condensation of the latter with diethyl ethoxymethylidenemalonate, as in the above-mentioned patent, cyclization, and ester hydrolysis gives 9,10-difluoro-3-[hydroxy-bis(diethoxyphosphono)methyl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, which is finally reacted with 1-methylpiperazine to yield 9-fluoro-3-[hydroxy-bis(diethoxyphosphono)methyl]-10-(4-methyl-l-piperazyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[F:10][C:11]1[CH:26]=[CH:25][C:14]([C:15](ON2C(=O)CCC2=O)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:10][C:11]1[CH:26]=[CH:25][C:14]([C:15](=[O:16])[CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8]#[N:9])=[CH:13][CH:12]=1
Reactant: N#CCc1ccncc1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C(=O)c1ccc(F)cc1)c1ccncc1
Temperature: 25 °C
Yield: 103 %

Procedure:
32 g of 4-pyridylacetonitrile and 86 g of 2,5-dioxo-pyrrolidinyl 4-fluorobenzoate were dissolved in 1.3 L of dimethylformamide. After the addition of 164 g of potassium carbonate, the resulting mixture was stirred at room temperature for a day. After the reaction mixture was filtered through cerite, the filtrate was concentrated under reduced pressure. After water was added to the residue, this solution was neutralized with an aqueous solution of hydrochloric acid. The precipitated crystals were collected by filtration, washed with diethyl ether, and then dried in a stream of air to obtain 67 g (103% yield) of the title compound.