Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:34])[CH:14]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:13]2[C:21]([CH3:33])=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:23]([CH3:26])=[C:24]([CH3:25])[C:12]=2[O:11]1.[ClH:35]>C(OCC)(=O)C>[ClH:8].[ClH:35].[CH2:1]([N:30]1[CH2:31][CH2:32][N:27]([C:22]2[C:23]([CH3:26])=[C:24]([CH3:25])[C:12]3[O:11][C:10]([CH3:34])([CH3:9])[CH:14]([N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)[C:13]=3[C:21]=2[CH3:33])[CH2:28][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCCC1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2N1CCCCC1
Yield: 64 %

Procedure:
Using Benzyl chloride and (2,2,4,6,7-pentamethyl-3-piperidino-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 152, the free base was obtained in the same manner as in Example 2. The free base was treated with a 4 N hydrogenchloride in ethyl acetate solution (10 ml) to obtain the title compound. Yield 64% Amorphous powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])CCC.[CH3:16][C:17]1([CH3:31])[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18]1>C1COCC1>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([C:22]2([OH:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:18][C:17]2([CH3:31])[CH3:16])=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2(C)C)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 5-bromo-2-chloro-anisole (1.613 g, 7.3 mmol) in THF (15 mL) at −78° C. was added n-butyl lithium (4.75 mL, 7.6 mmol, 1.6 M) dropwise over 15 min and the resulting solution was allowed to stir at −78° C. for 1 h. A solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (prepared in the manner described in International Patent Application WO 04/043965, 754 mg, 3.32 mmol) in THF (5 mL) was added dropwise via canula. The reaction was stirred for 2 h at −78° C. then allowed to warm to rt slowly over 30 min at which time the mixture was heated at 50° C. for 30 min. The reaction was cooled to rt, quenched by the addition of aq NH4Cl, diluted with water and extracted into EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified via column chromatography (15% to 33% to 50% EtOAc/heptane to afford tert-butyl 4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (728 mg, 60% yield).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C@H:7]([C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)[N:6]1[C:27](=[O:30])[CH2:28]Cl)=O.[CH3:31][NH2:32]>CO>[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([C@@H:7]3[C:8]4[NH:9][C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=5[C:16]=4[CH2:17][C@@H:5]4[C:3](=[O:2])[N:32]([CH3:31])[CH2:28][C:27](=[O:30])[N:6]34)=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CN
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccc3c(c2)OCO3)N1C(=O)CCl
Solvent: CO
Product: CN1CC(=O)N2[C@H](c3ccc4c(c3)OCO4)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Reaction time: 5 h

Procedure:
Cis-1-benzo[1,3]dioxol-5-yl-2-(2-chloro-acetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester of Step 3 (30 g) was taken in methanol (450 ml). The resultant mixture was heated to 35° C. to 40° C. and aqueous methyl amine (27 ml; 40%) was added. The reaction mixture was stirred at 50° C. to 55° C. for 5 hours and then cooled to 10° C. to 15° C. with continuous stirring for 0.5 hours. The solid so obtained was filtered and dried to afford (6R,12 aR)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1.[F-].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C([Sn](CCCC)(CCCC)[CH2:39][CH2:40][CH2:41][OH:42])CCC>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:39]=[CH:40]/[CH2:41][OH:42])[CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)CCCO
Reactant: CCOC(=O)c1noc(-c2cccc(Br)c2)c1N
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCOC(=O)c1noc(-c2cccc(/C=C/CO)c2)c1N
Temperature: 100 °C
Yield: 22.6 %

Procedure:
To a dioxane (4 mL) solution of compound from Example 21C (710 mg, 2.3 mmol) was added Pd3(dba)2-CHCl3 (71 mg, 0.07 mmol, 3% equiv.) and CsF (760 mg, 5.1 mmol, 2.2 equiv.) under N2. P(tBu)3 (10% in hexanes, 0.42 mL, 0.14 mmol, 12% equiv) and 3-tributylstannyl-1-propanol (1.1 g, 3.2 mmol, 1.1 equiv.) were added sequentially. The mixture was flushed with N2 for 2 min and then heated to 100° C. in a sealed culture tube. The mixture was purified by flash column chromatography (50% ethyl acetate in hexanes) to provide the titled compound (150 mg, 22%).
Reaction SMILES: [N+:1]([O:4][N+]([O-])=O)([O-:3])=[O:2].C([N:11]1[CH2:18][N:17]([N+]([O-])=O)[CH2:16][N:15](C(=O)C)[CH2:14][N:13]([N+]([O-])=O)[CH2:12]1)(=O)C>>[NH:11]1[CH2:18][NH:17][CH2:16][NH:15][CH2:14][NH:13][CH2:12]1.[N+:1]([O-:4])([OH:3])=[O:2]
Reactant: CC(=O)N1CN([N+](=O)[O-])CN(C(C)=O)CN([N+](=O)[O-])C1
Reactant: O=[N+]([O-])O[N+](=O)[O-]
Product: C1NCNCNCN1
Product: O=[N+]([O-])O

Procedure:
U.S. Pat. No. 4,432,902, issued to McGuire, et al. on Feb. 21, 1984, teaches the formation of HMX by addition of dinitrogen pentoxide (N2O5) to a solution of 1,5-diacetyl-3,7-dinitro-1,3,5,7-tetraazacyclooctane (DADN): ##STR2## or 1,3,5,7-tetraazacyclooctane (TAT) in an unspecified solvent (which is understood to be anhydrous nitric acid) to form a solution of HMX. The solution is then poured into a bath of water (in which HMX is insoluble) to cause the HMX to crystallize. While the McGuire patent uses the reaction scheme preferred herein, beta HMX is not consistently produced because the reaction conditions, particularly at the point where the HMX solution is added to water, are not precisely controlled. McGuire discloses that a concentrated acid should be added to water suddenly (Example 14) to precipitate HMX. This causes localized or general exotherms which encourage formation of undesired polymorphs of HMX. McGuire's method has been shown to be difficult to practice on a larger than laboratory scale.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@H:3]1[CH3:7].CS(C)=O.C(=O)([O-])O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:3]1[CH3:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1NCC[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a suspension of (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one (10.45 g) in dry THF (418 mL) was added dropwise Red-Al (104.9 g: 363 mmol: 70% toluene solution) under ice-cooling and a nitrogen stream. The mixture was stirred at room temperature for 20 min, and further refluxed for 3 hr. The reaction mixture was ice-cooled again, and sodium carbonate decahydrate (41.6 g) was added under a nitrogen stream. The mixture was stirred at room temperature overnight, insoluble materials were filtered through celite and washed with THF. The filtrate and washing were combined and concentrated under reduced pressure to give (2S,3S)-3-hydroxy-2-methylpyrrolidine. Without further purification, this compound was diluted with DMSO to give 0.9 mol/L-DMSO solution. A solution (170 mL) of (2S,3S)-3-hydroxy-2-methylpyrrolidine in 0.9 mol/L-DMSO was diluted with water (200 mL), sodium hydrogen carbonate (24.6 g) and benzyl chloroformate (15 mL) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield: 20.64 g, 84%).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5]C[CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:50])CC2)CC1>>[OH:50][CH:5]1[CH2:3][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6]1
Reactant: CC(C)Oc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: CC(C)Oc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-isopropoxy-1H-indole-2-carboxylic acid 74 (preparation see Example 2) and amine 21.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(O[C:35]([N:37](C)[C:38]1([C:42](O)=[O:43])[CH2:41][CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:42]([C:38]4([NH:37][CH3:35])[CH2:41][CH2:40][CH2:39]4)=[O:43])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CN(C(=O)OC(C)(C)C)C1(C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC1(C(=O)N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol), 1-(tert-butoxycarbonyl(methyl)amino)cyclobutanecarboxylic acid (27.5 0.12 mmol), HATU (45.8 mg, 0.12 mmol) and di-isopropylethylamine (20 μL, 0.12 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA, and was stirred for 2 h followed by concentration in vacuo. The crude product was purified by RP-HPLC to afford (4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(1-(methylamino)cyclobutyl)methanone; ESMS m/z 527.2 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].II>>[CH3:1][N:2]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CNc1cccc(F)c1
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Product: CN(Cc1ccc(Cl)cc1)c1cccc(F)c1

Procedure:
N-methyl-N-p-chlorobenzyl-m-fluoroaniline was prepared from 17.5 grams (0.14 mole) of N-methyl-m-fluoroaniline, 23.7 grams (0.14 mole) p-chlorobenzyl chloride (Aldrich), 11.9 grams anhydrous sodium acetate and 0.12 grams iodine according to the procedure as described in Example III. Yield 25.8 grams (74 percent), boiling point 162°-170° C. at 0.13 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(OC([N:20]1[CH2:25][CH2:24][C:23]2([CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1)=O)(C)(C)C>>[CH2:22]1[C:23]2([CH2:30][CH2:29][CH:28]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)[CH2:27][CH2:26]2)[CH2:24][CH2:25][NH:20][CH2:21]1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Product: O=c1ccc2ccc(OC3CCC4(CCNCC4)CC3)cc2o1

Procedure:
Was prepared according to method A from 7-hydroxycoumarin and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH2:23][CH2:22]1>CN(C)C=O>[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Reaction time: 6 h
Yield: 60 %

Procedure:
In 30 ml of dimethylformamide were dissolved 2.6 g of 5-fluorouracil, 2.66 g of anhydrous aluminum chloride and 7.0 ml of triethylamine. The reaction was carried out at 130° C. for 6 hours while adding 3.0 ml of 2,3-dihydrofuran to the solution. The reaction liquid was treated in the same manner as described in Example 13 to obtain 2.4 g of (1-(2-tetrahydrofuryl)-5-fluorouracil. The yield was 60%.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][NH2:12].CO.[I-].[Na+]>C(O)C>[CH3:11][NH:12][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: CN
Reactant: OCCOCCOCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CNCCOCCOCCO
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-[2-(2-Chloro-ethoxy)-ethoxy]-ethanol (2.00 mL, 13.8 mmol) was dissolved in ethanol (14.0 mL). A solution of methylamine in methanol (40%, 14.0 mL, 138 mmol) and sodium iodide (103 mg, 0.67 mmol) were added, and the mixture was stirred at 60° C. for 18 hours and then stirred at 75° C. for seven hours in a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to give 2-[2-(2-methylamino-ethoxy)-ethoxy]-ethanol as a crude product.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@@H:8]2[OH:17])[CH2:4][O:3]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[O:6][CH:5]([CH:7]2[O:11][CH:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][CH:9]3[CH:8]2[O:17][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][O:3]1
Reactant: BrCc1ccccc1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@@H](O)[C@H]2O1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C)OCC(C2OC3OC(C)(C)OC3C2OCc2ccccc2)O1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 1,2:5,6-Di-O-isopropylidene-α-D-allofuranose (30A) (obtained from Pfanstiehl Laboratories Inc.) (40 g) in dimethylformamide at 0° C. was added sodium hydride in smaller portions. The reaction mixture was stirred for 1 h, benzyl bromide was added drop wise over a period of 1 h. The reaction mixture was stirred at room temperature for 16 h. Methanol was added to quench the reaction and dimethylformamide was removed under pressure. The syrup was extracted with ethyl acetate and washed with brine. Evaporation of the ethyl acetate layer yielded a semisolid (93%). Homogeneous by TLC.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[CH2:40]([Si:42](Cl)([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41].C(OCC)(=O)C.O>N1C=CC=CC=1>[CH3:41][CH2:40][Si:42]([O:37][C@@H:8]1[C@@:7]2([CH3:38])[C:5]([C@H:4]([OH:39])[C:3]3[C:15]([CH3:16])([CH3:17])[C@:14]([OH:21])([C@@H:13]([O:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])[C@@H:12]2[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9]1)[CH2:18][C@H:19]([OH:20])[C:2]=3[CH3:1])=[O:6])([CH2:45][CH3:46])[CH2:43][CH3:44]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reactant: CC[Si](Cl)(CC)CC
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@H]1C[C@H]2OC[C@@]2(OC(C)=O)[C@H]2[C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C([C@@H](O)C(=O)[C@]12C)C3(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 77.8 %

Procedure:
544 mg (1 mmol) of 10-deacetylbaccatine III, dissolved in 50 cm3 of anhydrous pyridine, are introduced under an argon atmosphere into a 100-cm3 round-bottomed flask equipped with a magnetic stirrer. 3.36 cm3 (3.014 g; 20 mmol) of triethylsilyl chloride are then added. The homogeneous, yellow reaction mixture is then stirred for 24 hours at 0° C. Ethyl acetate and water are then added. After settling has taken place, the separated aqueous phase is extracted with ethyl acetate. The combined organic phases are treated with saturated aqueous copper sulphate solution until the pyridine has been completely removed. The organic phases are washed with water and then with saturated sodium chloride solution, and then dried over anhydrous sodium sulphate. After filtration and evaporation of the solvents under reduced pressure, 2.73 g of a product are obtained, and this is purified on a silica column, eluting with a dichloromethane/methanol (99:1 by volume) mixture. 512 mg (0.778 mmol) of 10-deacetyl-7-triethylsilylbaccatine III are thereby obtained, in a 78% yield, in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([CH2:16][C:17]([OH:19])=O)[C:6]1=[O:20].Cl.[CH3:23][NH:24][CH3:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:23][N:24]([CH3:25])[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[C:6]1=[O:20]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)O)c2cc(C)cc(C)c21
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)Cn1c(=O)n(CC(=O)N(C)C)c2cc(C)cc(C)c21

Procedure:
A solution of [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (Intermediate 9) (305 mg, 1.04 mmol), N,N-dimethylamine hydrochloride (128 mg, 1.60 mmol), EDC (300 mg, 1.60 mmol), HOBT (240 mg, 1.60 mmol), and N,N-diisopropylethylamine (0.909 mL, 5.20 mmol) were stirred for 16 h at ambient temperature in DMF (3 mL): The mixture was partitioned between CH2Cl2 (10 mL) and saturated NaHCO3 (10 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated to give the compound. MS: m/z=320 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([CH:8]([F:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3](OCC)=[O:4].[BH4-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[F:1][C:2]([F:19])([CH:8]([F:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C(F)C(F)(F)CO)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82.1 %

Procedure:
To a solution of ethyl 2,2,3-trifluoro-3-(3-nitrophenyl)propanoate (C30, 1.19 g) in ethanol (43 mL), sodium borohydride (811 mg) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, ethyl acetate and 1.0 mol/L aqueous hydrochloric acid were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 40% hexane in ethyl acetate) to obtain 2,2,3-trifluoro-3-(3-nitrophenyl)propan-1-ol (C31, 829 mg).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([N:24]2[CH:28]([C:29]([O:31]CC)=[O:30])[CH2:27][S:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S1CC(C(O)=O)NC1>C(=O)(O)[O-].[Na+].CC(C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH:28]([C:29]([OH:31])=[O:30])[CH2:27][S:26][CH2:25]2)=[O:23])=[CH:34][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N2CSCC2C(=O)OCC)cc1
Agent: O=C(O)C1CSCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N2CSCC2C(=O)O)cc1

Procedure:
By means of the alkaline hydrolysis method of Example 7, the ethyl ester of Example 21 is converted to the subject carboxylic acid. This acid is also prepared using the procedure of Example 21 except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)=[C:40]([CH:44]=1)[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:45]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)=[C:40]([C:41]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:7]3)[CH2:2]2)=[O:42])[CH:44]=1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1cc(F)ccc1-c1ncccn1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-pyrimidin-2-yl-benzoic acid for 2-thiophen-2-yl-benzoic acid Additionally, the reaction time was shortened to 30 minutes. MS (ESI) mass calcd. for C25H21FN6O, 440.48; m/z found 441.2 [M+H]+.