Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:30])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:17])[CH2:13][CH2:12][N:11]([C:31]([C@H:33]3[CH2:38][CH2:37][O:36][CH2:35][C@H:34]3[NH:39]C(=O)OC(C)(C)C)=[O:32])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>Cl.CC(O)C>[ClH:1].[NH2:39][C@H:34]1[C@@H:33]([C:31]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]([CH3:30])[C:16](=[O:17])[C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10]2)=[O:32])[CH2:38][CH2:37][O:36][CH2:35]1
Reactant: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)[C@H]2CCOC[C@H]2NC(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)[C@H]2CCOC[C@H]2N)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 249.5 %

Procedure:
A solution of tert-butyl [(3S,4S)-4-{[(3R,4R)-3-(3,4-dichlorophenyl)-4-{methyl[(4-morpholin-4-ylphenyl)carbonyl]amino}piperidin-1-yl]carbonyl}tetrahydro-2H-pyran-3-yl]carbamate (200 mg) obtained in Example 627 in 2N hydrogen chloride/2-propanol (5 mL) was stirred at 55° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (226 mg, 100%) as a white powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12]>>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1cccc2ccccc12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
89.6 g naphthalene (0.7 m) and 70 g sulfuric acid 98% (0.7 m) were charged to a reactor and mixed. The mixture was then heated rapidly to 150° C. and agitated at 150° C. for 2 hours. Then 30 g sulfuric acid 98% (0.3 m) was added and agitated for an additional hour at 150° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][CH:7]=1>C(O)=O>[CH3:13][N:12]([CH3:14])[C:10]1[N:11]=[C:6]([CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)c1cccc(C2OCCO2)n1
Solvent: O=CO
Product: CN(C)c1cccc(C=O)n1
Temperature: 60 °C

Procedure:
0.60 g of (6-[1,3]dioxolan-2-yl-pyridin-2-yl)dimethylamine (3.09 mmol) is mixed in 10 ml of an aqueous solution of formic acid at 80% and then the solution is heated at 60° C. for 20 hours. The solvents are removed by azeotropic entrainment with toluene, the residue is taken up in water, the mixture is cooled to 0° C. and then the medium is basified by addition of potassium carbonate. The mixture is extracted with ethyl acetate, the organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and the solvent is evaporated under vacuum. The title product is obtained in the form of a yellow oil (0.43 g) which is used in the next stage without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:38])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][C:33]([F:36])([F:35])[F:34])[N:20]=[CH:21][C:22]=2[CH:23]2[CH2:25][CH2:24]2)=[CH:12][C:11]=1[CH3:37])([CH3:6])([CH3:5])[CH3:4].I[CH3:40]>CN(C=O)C>[C:3]([O:7][C:8](=[O:38])[N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][C:33]([F:36])([F:34])[F:35])[N:20]=[CH:21][C:22]=2[CH:23]2[CH2:25][CH2:24]2)=[CH:12][C:11]=1[CH3:37])[CH3:40])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
Sodium hydride (60% in mineral oil, 183 mg, 4.58 mmol) is added to a solution of {4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-carbamic acid tert-butyl ester (1.92 g, 3.81 mmol) and DMF (15 mL) in an ice bath. The mixture is stirred for 30 minutes and iodomethane (0.36 mL, 5.7 mmol) is added. The bath is removed and the mixture is stirred for 1 h and quenched with a mixture if ice and ammonium chloride. The mixture is diluted with ethyl acetate and water. The organic layer is washed with brine and dried over MgSO4 to provide 1.94 g (98%) of the title compound as an oil. LC-ES/MS m/e 518.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:14]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]2)=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([O:10]C)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[C:14]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:22])[F:23])[C:17]([CH3:24])=[N:16]2)=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([OH:10])=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)c(-n2nc(C)n(C(F)F)c2=O)cc1OC(C)C(=O)O
Yield: 84.8 %

Procedure:
In a manner similar to Example 2, Step H, the reaction of 3.3 g (0.0088 mole) of methyl 2-[4-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-2-methylphenoxy]propionate with 1.5 g (0.27 mole) of potassium hydroxide in 50 mL of ethanol and 15 mL of water produced 2.7 g of 2-[4-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-2-methylphenoxy]propionic acid as a solid (mp 56°-60° C.), Compound A3.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[N:1]1([CH2:6][CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)/C=C/c1ccccc1COCCN1CCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1COCCN1CCCC1
Yield: 97.1 %

Procedure:
A mixture of ethyl (2E)-3-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)-2-propenoate (8.27 g, 27.3 mmol) and 5% Pd/C (800 mg) in ethanol (50 ml) was hydrogenated under a hydrogen balloon for 3 h The reaction mixture was filtered through a pad of celite and the resulting Pd/C on the celite pad was washed with ethanol. The filtrate was evaporated in vacuo to afford the titled compound (8.10 g, 97.2%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].CCO>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
1-(4-nitrophenyl)piperidin-4-ol (4.725 g, 21.26 mmol), Fe (11.87 g, 212.6 mmol), NH4Cl (11.41 g, 212.6 mmol), EtOH (100 mL) and water (50 mL) were mixed. The mixture was stirred at 100° C. overnight. Then Fe (5.9 g, 106.3 mmol) was added and reacted at 100° C. for 7 hours. Filtrated and the liquid was concentrated, purified by flash chromatography to give 1.8 g yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[O:20][CH3:21])=[O:5])C.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>>[CH:17]([N:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:9]=3[N:8]=[CH:7][C:6]=2[C:4](=[O:5])[N:25]([CH:22]([CH3:24])[CH3:23])[C:26]1=[O:27])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC(C)C
Reactant: CC(C)N=C=O
Product: COc1cccc2c1ncc1c(=O)n(C(C)C)c(=O)n(C(C)C)c12
Yield: 32.1 %

Procedure:
1,3-Diisopropyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (59.6 mg, 0.20 mmol) and isopropyl isocyanate (1.0 mmol) following general procedure C. LCMS: m/z 328 [M+1]+.
Reaction SMILES: C(OC(OC(OCC)=O)=O)C.C(OC([N:17]1[C:25]([NH2:26])=[C:24]2[C:19]([C:20]([N+:31]([O-:33])=[O:32])=[CH:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23]2)=[N:18]1)=O)C>C(O)C>[NH2:26][C:25]1[C:24]2[C:19](=[C:20]([N+:31]([O-:33])=[O:32])[CH:21]=[C:22]([C:27]([F:30])([F:28])[F:29])[CH:23]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)n1nc2c([N+](=O)[O-])cc(C(F)(F)F)cc2c1N
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCO
Product: Nc1n[nH]c2c([N+](=O)[O-])cc(C(F)(F)F)cc12

Procedure:
Analogously to Example 1, 0.1 mol of 3-amino-5-trifluoromethyl-7-nitroindazole and 150 ml of pyrocarbonic acid diethyl ester in 100 ml of ethanol give 3-amino-5-trifluoromethyl-7-nitro indazole-2-carboxylic acid ethyl ester (melting point: 186°-187° C; 74% of theory) in 30 minutes at 80° C.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.O[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.CO>[O:6]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:1][O:7][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCC1CCCO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a solution of tetrahydrofurfuryl alcohol (25 g), methyl 4-hydroxybenzoate (38 g), and triphenylphosphine (72 g) in tetrahydrofuran (300 mL) was slowly added dropwise a solution of diethyl azodicarboxylate in toluene (136 mL, 40% toluene solution) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and triphenylphosphine oxide was precipitated from ethyl acetate-hexane. Triphenylphosphine oxide was removed by filtration with a glass filter, and the mother liquor was concentrated. The residue was purified by silica gel column chromatography [developing solvent; hexane:ethyl acetate=100:0 (volume ratio)→hexane:ethyl acetate=70:10 (volume ratio)] to give a colorless oil. The obtained colorless oil was dissolved in tetrahydrofuran (200 mL) and methanol (100 mL), 8N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was stirred at 80° C. for 2 hr with heating. The reaction solution was concentrated, cooled to 0° C., neutralized with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (17 g, yield 31%) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].Cl[C:8]([O:10][CH2:11][CH:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9].O>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:8]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([O:10][CH2:11][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[C:24]1=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:9]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Yield: 90.1 %

Procedure:
To a solution of L-alanine (1.78g, 20 mmol) in 10% Na2CO3 (53 ml) was added dropwise (within 50 min) with stirring and ice bath cooling a solution of 9-fluorenylmethyl chloroformate (5.17g, 20 mmol) in dioxane (40 ml). The mixture was stirred for 1 hr at 0° and 15 hr at 5°, poured into H2O (1.5 liters) and extracted with ether (2 x). The aqueous layer was cooled in an ice bath, acidified with concentrated HCl to pH 2-3 (white precipitate) and extracted with EtOAc (3 × 500 ml). The organic phase was washed with H2O, dried (MgSO4), filtered, and evaporated. Ether-petroleum ether was added to the residue which crystallized while being kept at 5°. The crude product (5.94g, 95.5%) was recrystallized from methanol-petroleum ether to yield colorless crystals of Fmoc-L-alanine (5.61g, 90.2%), mp 144.5°-145.5° ; [α]D25 = - 11.7° (c 1, CH3OH); tlc, Rf 0.8 (A), 0.3 (B); uv max (CH2Cl2) 267 nm (ε18,950), 290 (5,280), 301 (6,200).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:6]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:17])[F:18])[C:7]2=[O:20])[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Product: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 18, 200 mg) by alkylation with bromomethylcyclopropane (105 mg). 3-Cyclopropylmethyl-4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (72 mg). MS (ESI): 339.2 (MH+).
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[C:4](=[O:11])[NH:3][CH:2]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:19][C:18]1[C:13]([N:8]2[CH2:9][CH2:10][C:5]3[C:4](=[O:11])[NH:3][CH:2]=[N:1][C:6]=3[CH2:7]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccnc1Cl
Reactant: O=c1[nH]cnc2c1CCNC2
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]cnc2c1CCN(c1ncccc1Cl)C2
Temperature: 150 °C
Yield: 85.7 %

Procedure:
5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (600 mg, 4.0 mmol) was dissoled in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (1.8 g, 12.0 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.0 mmol). The mixture was heated at 150° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a yellow solid (900 mg, 86%), which was used as such for the next step.
Reaction SMILES: [BH4-].[Na+].[N:3]([C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][C@H:7]1OS(C1C=CC(C)=CC=1)(=O)=O)=[N+]=[N-].N([C@H]1[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)CCN(C(OCC2C=CC=CC=2)=O)C1)=[N+]=[N-].[P:63](Cl)(=[O:70])([O:67][CH2:68][CH3:69])[O:64][CH2:65][CH3:66]>CO.C(Cl)Cl.O>[CH2:65]([O:64][P:63]([N:3]1[CH:7]2[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH2:8]2)([O:67][CH2:68][CH3:69])=[O:70])[CH3:66]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]2N=[N+]=[N-])cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2N=[N+]=[N-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
NaBH4 (3.41 g, 90.3 mmol) was added portion wise to a solution of CuSO4.5H2O (10.73 g, 42.98 mmol) in methanol (200 mL) at 0° C. After 5 minutes, a solution of trans-benzyl 4-azido-3-(tosyloxy)piperidine-1-carboxylate and trans-benzyl 3-azido-4-(tosyloxy)piperidine-1-carboxylate (37 g, 85.95 mmol; mixed product from last step) in methanol (100 mL) was added at 0° C. After addition, additional NaBH4 (10.2 g, 270.6 mmol) was added in four portions over the course of 1 hour. After one hour at 0° C., the reaction mixture was filtered through a pad of celite and concentrated in vacuo. The residue obtained was dissolved in DCM (800 mL), washed with water (200 mL), saturated NH4Cl solution (200 mL), brine (200 mL), dried (sodium sulfate) and concentrated in vacuo. The residue obtained was dissolved in DCM (200 mL) and TEA (24.0 mL, 171.9 mmol) and diethyl phosphorochloridate (12.4 mL, 85.95 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. Water (50 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (17.5 g, 55%) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])=[N:7][CH:8]=1)=O.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].N1CCCCC1.C(O)C>O>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][CH2:10][O:9][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[C:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:8][N:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cn1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)cn1
Yield: 29.3 %

Procedure:
A mixture of 5-formyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]pyridine (0.6 g), 2,4-thiazolidinedione (0.235 g), piperidine (0.066 ml) and ethanol (20 ml) was heated for 9 hours while refluxing. The reaction mixture was poured into water; the separating crystal, collected by filtration, was then recrystallized from ethanol-chloroform to yield 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methylidene]-2,4-thiazolidinedione (0.232 g, 29%) as a yellow crystal.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].Cl[C:16]1[C:21]2=[N:22][O:23][N:24]=[C:20]2[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][CH:3]([CH2:2][S:1][C:16]1[C:21]2[C:20](=[N:24][O:23][N:22]=2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][CH:17]=1)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(CSc1ccc([N+](=O)[O-])c2nonc12)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
700 Mg of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline, 700 mg of 4-chloro-7-nitrobenzofurazan (10% excess), 1 g sodium bicarbonate, and 10 ml dichloromethane were stirred at 20° C. for 16 hours. The reaction mixture was put in a 4×30 cm Silicar CC4 column, and eluted with C6H6 :CH3COOH (3:1) mixture (v/v).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N+:15]([O-])=O)[CH:8]=2)[CH2:3][CH2:2]1>CO.[Pd]>[NH2:15][C:9]1[CH:8]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(N2CCOCC2)cc1N

Procedure:
A solution of 4-morpholino-2-nitrobenzonitrile (300 mg, 0.24 mmol) in MeOH (140 mL) was reduced using a continuos flow hydrogenation reactor (flow rate: 1 mL/min, 10% mol Pd/C, temperature 40° C., H2 pressure: 10 atm) to give 2-amino-4-morpholinobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11](=[O:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH:17]([F:19])[F:18]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:17]([F:19])[F:18])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)=NO1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: FC(F)Oc1cc(-c2ccc(Cl)cc2)no1
Temperature: 0 °C

Procedure:
In a 100 ml autoclave, 5.87 g (0.03 mol) 3-(4-chlorophenyl)-5-(4H)-isoxazolone was dissolved 30 ml dioxane and treated with 10 ml of 30% aqueous potassium hydroxide. The autoclave was pressurised to 10 bar with chlorodifluoromethane and the reaction mixture was heated at 50°-60° C. for 15 hours. After cooling and reducing the pressure the solution was poured into 300 ml ice/water and extracted three times with 70 ml ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by column chromatography.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>C1COCC1>[Cl:15][C:16]1[N:21]=[C:20]([C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:19]([F:23])=[CH:18][N:17]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(=O)OCC)c1nc(Cl)ncc1F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
(Prepared according to Butters, M. et al. Org. Proc. Res. Dev. 2001, 5, 28-36). Diethyl 2-methylmalonate (2.35 mL, 13.78 mmol) was treated with THF (80 mL) and cooled to −10° C. in a brine/ice bath. It was then treated with NaH (60 wt % suspension in mineral oil, 1.10 g, 27.6 mmol) and stirred at this temperature for 30 min. 2,4-Dichloro-5-fluoropyrimidine (2.00 g, 11.98 mmol) was suspended in THF (20 mL) and added to the cooled solution via pipette over 10 min. The solution turned an opaque yellow color. After stirring 20 min at −10° C. it was quenched by the addition of H2O (100 mL), DCM (150 mL) and glacial HOAc (ca. 1 mL to pH 6). The DCM layer was then separated and dried over MgSO4, filtered and concentrated affording a viscous oil. Purification with flash chromatography (eluting with 100% DCM) afforded diethyl 2-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylmalonate (3.04 g, 83%) as a pale yellow viscous oil. MS (ESI, pos. ion) m/z: 305.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.44 (1H, d, J=2.0 Hz), 4.24-4.33 (4H, m), 1.90 (3H, s), 1.24-1.33 (9H, m).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33]O)[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.CP(C)C.[NH4+].[OH-]>O1CCCC1.O>[NH2:51][CH2:33][C:31]1[S:30][CH:29]=[C:28]([CH:27]=[C:26]([CH:10]2[O:11][C:12](=[O:13])[CH2:14][CH:15]([OH:25])[C:16]([CH3:24])([CH3:23])[C:17](=[O:18])[CH:19]([CH3:22])[CH:20]([OH:21])[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]3([CH3:36])[CH:7]([O:8]3)[CH2:9]2)[CH3:35])[N:32]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: CP(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(=Cc1csc(CN)n1)C1CC2OC2(C)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1
Reaction time: 0.17 h
Yield: 120.6 %

Procedure:
To a stirred suspension of epothilone F (47.12 g, 90.0 mmol) in tetrahydrofuran (942 ml, previously dried over 3A molecular sieves) under argon, was added diphenylphosphoryl azide (29.2 ml, 37.3 g, 135.5 mmol, 1.5 equivalents). The mixture was stirred for about 10 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (24.5 ml, 24.94 g, 163.8 mmol, 1.8 equivalents) was then added gradually, at a rate that maintained the temperature of the mixture below 30° C. The mixture was stirred for 22 hours. To the reaction mixture was added a solution of trimethylphosphine in tetrahydrofuran (1.0 M, 99.0 ml, 86.3 g, 99.0 mmol, 1.1 equivalents), at a rate that maintained the temperature of the mixture below 30° C. The mixture was stirred at room temperature for 30 minutes, and water (244 ml) was added. After 30 minutes, 28% aqueous NH4OH (125.0 ml) was added, and the mixture stirred for 30 minutes. Water (470 ml) was added, and the mixture was extracted with methylene chloride (3×100 ml). The combined organic extracts were washed with aqueous ammonium hydroxide (1.0 M, 3×470 ml). NMR analysis was used to determine the presence of residual diphenylphosphate in the organic phase. The organic phase was then washed with half-saturated aqueous sodium chloride (470 ml), the solvents were removed on a rotary evaporator, and the residual solid was dried in vacuo for 18 hours to afford the crude product (56.72 g, 120.6% yield).