Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:13]2[CH:12]=[C:7]3[C:8]4[C:3]([CH2:4][CH2:5][N:6]3[C:16](=[O:17])[CH2:15][N:14]=2)=[C:2]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:11]=[CH:10][CH:9]=4)[CH:23]=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COc1cccc(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COc1cccc(C2=NCC(=O)N3CCc4c(cccc4-c4ccccc4)C3=C2)c1
Temperature: 140 °C
Yield: 65.2 %

Procedure:
A mixture of 9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 30) (250 mg, 0.56 mmol), tributyl(phenyl)stannane (202 μL, 1.10 mmol) and Pd(PPh3)4 (33 mg, 0.03 mmol) in 1,4-dioxane (4 mL) was heated in a microwave reactor at 140° C. for 1 h. The mixture was then filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography (SiO2, hexane to hexane/AcOEt 3:1) to give a yellow oil that was recrystallized from heptane to afford the title compound (144 mg) as white solid. UPLC-MS: MS 395.1 (M+H+); UPLC rt 1.20 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 2.90 (t, J=6.06 Hz, 2 H); 3.79 (t, J=6.26 Hz, 2 H); 3.86 (s, 3 H); 4.53 (br. s., 2 H); 6.97 (s, 1 H); 6.97-7.04 (m, 1 H); 7.28-7.37 (m, 3 H); 7.37-7.51 (m, 7 H); 7.68 (t, J=4.50 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCn1ccc2ccc(Br)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCn1ccc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Yield: 56.1 %

Procedure:
Following the procedure described in Step 2 of Example 2, 6-bromo-1-ethyl-1H-indole (0.400 g , 1.78 mmol), was coupled to 4-trifluoromethylbenzene boronic acid (0.348 g, 1.83 mmol), using tetrakis(triphenylphosphine)palladium (0.0668 g, 0.0578 mmol), and sodium carbonate (0.769 g, 7.26 mmol) in water (3.6 mL), ethanol (1.5 mL), and toluene (8 mL). Purification by flash chromatography using hexane as an eluant yielded the title compound as a yellow oil (0.289 g, 56%). 1HNMR (300 MHz, DMSO-d6): δ 7.95 (d, 2H, J=7.7 Hz), 7.9 (s, 1H), 7.8 (d, 2H, J=7.7 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.5 (d, 1H, J=1.5 Hz), 7.45 (d, 1H, J=7.7 Hz), 6.45 (d, 1H, J=2.3 Hz), 4.3 (q, 2H, J=6.9 Hz) and 1.4 ppm (t, 3H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:19]=[C:20](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:20](=[O:19])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc(N)c(C(=O)O)c2)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC1

Procedure:
To the mixture of 5.3 g of 2-amino-5-(4-methylpiperazino)benzoic acid in 30 mL of dioxane, under stirring and external cold water cooling 6 mL of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 mL of ether. The product is stirred for 5 minutes in the mixture of 50 mL of methanol and 5 mL of triethylamine, filtered off, washed with 30 mL of methanol. After drying 5.4 g of the title product is obtained, m.p.: 285° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C@@H:3]([OH:22])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:6]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.[N-]=C=O>C1(C)C=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C@@H:3]([O:22][C:33](=[O:34])[NH:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=2)[CH2:6]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O[C@@H](CN1CCO[C@H](c2ccc(F)c(C(F)(F)F)c2)C1)C(F)(F)F
Agent: [N-]=C=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCO[C@H](c2ccc(F)c(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(S)-1,1,1-Trifluoro-3-((R)-2-(4-fluoro-3-(trifluoromethyl)phenyl)morpholino)propan-2-ol (427 mg, 1.18 mmol) was mixed with 1-chloro-4-isocyanatobenzene (180 mg, 1.17 mmol) in toluene (5 mL). The mixture was stirred at 90° C. for 2 h. TLC indicated still significant amount of the starting material. So a second batch of 1-chloro-4-isocyanatobenzene (180 mg, 1.17 mmol) was added and the mixture was further stirred at 95° C. for 2 h. TLC indicated still significant amount of starting material. A second batch of isocyanate was added and the mixture was stirred at 90° C. for 2 h. The mixture was concentrated and the residue was extracted with ethyl acetate and water, washed with sodium bicarbonate solution and brine, dried and concentrated. The residue was purified through ISCO flash column chromatography (ethyl acetate in hexanes 0% to 40% gradient in 16 min). The desired fraction was concentrated to give (4-chlorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(4-fluoro-3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester a colorless oil, which was dissolved in ether and 1N HCl in ether (1 mL) was added. Solvent was evaporated and the residue was dissolved in ether. Hexane was added and solvents were evaporated to give a white solid 241 mg. LC/MS indicated 13% des-fluoro ((M+H)+=497 m/e) and 87% desired compound ((M+H)+=515 m/e).
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH2:19])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2F)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH:19][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:2]1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: NC(=NOCC1CC1)c1c(F)cccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)NC(=NOCC2CC2)c2ccccc2C(F)(F)F)cc1
Yield: 75.2 %

Procedure:
In 80 ml of benzene was dissolved 10.4 g of N'-cyclopropylmethyloxy-2-fluoro-6-trifluoromethylbenzamidine, and to the solution was added 8.9 g of 4-methoxyphenylacetylchloride. The solution was heated under refluxing for 3 hours. After cooling, ethyl acetate was added to the solution, followed by washing with water and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue obtained in crystal was washed with a mixed solvent hexane and ether to thereby obtain 13.7 g of crude crystal. The crystal was then re-crystallized in hexane, thereby affording 11.5 g of the objective compound.m.p. 88-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C@H:8]([C:10]([OH:12])=[O:11])N)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].C(=O)([O-])[OH:25].[Na+].O1CCO[CH2:31][CH2:30]1>>[OH:25][C@H:8]([CH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10]([O:12][CH2:30][CH3:31])=[O:11]
Reactant: C1COCCO1
Reactant: O=C([O-])O
Reactant: COc1ccc(C[C@@H](N)C(=O)O)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@H](O)Cc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Commercially available O-methyl-D-tyrosine (5.00 g) was dissolved in 1,4-dioxane (62.5 ml), and thereto were added successively dropwise an aqueous sulfuric acid solution (5.4 g/17.5 ml of water) and an aqueous sodium nitrite solution (6.3 g/15.0 ml of water) under ice-cooling, and the mixture was stirred at room temperature. Ten hours later, to the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium hydrogen sulfate, filtered, and concentrated under reduced pressure. The resultant was duly dried, and then, the obtained residue was dissolved in ethanol (50 ml), and further thereto was added conc. sulfuric acid (200 μL). The mixture was refluxed for 15 hours, and the reaction solution was added dropwise into ice-water (50 ml), and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=5/1) to give the title compound (3.40 g) as a colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]([F:18])([F:17])C(OC)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:17][CH:12]([F:18])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
4-Nitrophenol (0.14 g, 1.0 mmol, Aldrich), methyl chlorodifluoroacetate (0.29 g, 2.0 mmol, Aldrich) and potassium carbonate (0.29 g, 2.1 mmol) were combined in dry DMF (0.5 mL) under an argon atmosphere. After stirring at 95°-100° C. for 0.5 h, the mixture was cooled to RT, ethyl acetate (20 mL) was added and the organic layer was washed three times with 10% NaOH. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ether/hexanes) to provide the title compound as a white solid (0.12 g, 65%). mp 33°-35° C.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:53]([O:57][CH:58]=[CH2:59])[CH2:54][CH2:55][CH3:56]>C(O)CO.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:53]([O:57][C:58]([C:2]1[C:3]([F:23])=[C:4]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:59])[CH2:54][CH2:55][CH3:56]
Reactant: C=COCCCC
Reactant: COCN(c1cccc(Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: OCCO
Product: C=C(OCCCC)c1cccc(N(COC)S(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 6.15 g (15 mmol) of N-(3-bromo-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide in 35 mL of ethylenglycol in a flask equipped with a rubber septum, through which nitrogen is fluxed by a needle, 37.5 mg (0.15 mmol) of palladium acetate, 129 mg (0.30 mmol) of DPPP, 5.4 mL (37.5 mmol) of TEA and 5.9 mL (45 mmol) of n-butylvinylether were added consecutively. The mixture was heated at 120° C. under stirring for 6 h and then diluted with DCM and washed with brine. The organic layer was dried over Na2SO4 and evaporated, giving N-[3-(1-butoxyethenyl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide as a brown oil. The latter, without any further purification, was dissolved in 65 mL of 1,4-dioxane and 11 mL of 1N HCl were added to the resulting solution. After 1 h under stirring at r.t. the reaction was complete. The solvent was then removed, the residue re-dissolved with DCM and washed with aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated. After trituration with diethylether 4.82 g (86%) of the title compound were collected by filtration.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)CCCC2
Temperature: 70 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (10.0 g, 48.73 mmol), tin(II) chloride dihydrate (49.48 g, 219.3 mmol) and ethanol (200 ml) was stirred at 70° C. for 2 hours. The reaction mixture was poured into ice water, adjusted to pH 10 with sodium hydroxide, and then extracted with toluene. The extract solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 8.08 g of 3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[OH:28][CH2:27]/[CH:26]=[CH:25]/[C:16]1[C:15](=[O:30])[N:14]2[CH:31]=[CH:32][C:11]([CH2:10][CH2:9][C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)=[CH:12][C:13]2=[N:18][C:17]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)n1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/CO)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl}-2-propenoic acid (222.7 mg, 0.49 mmol) dissolved in tetrahydrofuran (8 ml) was added with triethylamine (342 μl) and ethyl chloroformate (141 μl) at −20° C., then stirred at room temperature for 1 hour, and subsequently added with aqueous sodium borohydride (0.8 M, 4 ml) at room temperature. The aqueous sodium borohydride was occasionally added until the reaction was completed, and the completion of the reaction was confirmed by TLC. Then, the reaction solution was added with water and extracted with chloroform and chloroform:methanol=10:1, and the organic layer collected was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1→60:1→30:1) to recover 81 mg (37%) of the title compound and 82 mg of the starting material.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:22])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A slurry of 4-acetoxybenzoic acid (100 g, 555.1 mmol) in CH2Cl2 (50 mL) was treated with a catalytic amount of DMF (0.5 mL) and cooled in ice bath. The reaction was stirred as neat oxalyl chloride (51 mL, 582.82 mmol, 1.05 equiv.) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give 4-(chlorocarbonyl)phenyl acetate (110 g, 100% th.; 110% pract.), which was used in the next step without further purification; 1H NMR (CDCL3) δ 8.09 (d, 2H), 7.20 (d, 2H), 2.28 (s, 3H) ppm.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[C@H:21]1[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54](O)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:21]1[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1COCc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)[C@H]1COCc1ccccc1
Reaction time: 14 h
Yield: 78.5 %

Procedure:
A solution of 0.52 ml (3.31 mmol) of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was slowly added at room temperature to a solution of 1.00 g (3.25 mmol) of (2R, 3R)-1-t-butoxycarbonyl-2-benzyloxymethyl-3-hydroxypyrrolidine [prepared as described in step (a) above], 0.87 g (3.31 mmol) of triphenylphosphine and 0.42 g (3.47 mmol) of benzoic acid in 5 ml of tetrahydrofuran, and the mixture was stirred for 14 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash chromatography through silica gel, using a 20:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.05 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C.CCCCCC>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([NH:41][C:42](=[O:43])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][N:19]([CH:22]5[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:29][CH:30]=2)=[O:40])=[CH:36][CH:37]=1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)CC1
Reaction time: 3.5 h
Yield: 49 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (834 mg) in tetrahydrofuran (45 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (0.25 M, 15 ml) at room temperature, followed by stirring for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (8 ml) and hexane (16 ml). The crystals were filtered off and dried under aeration to provide the titled compound (546 mg, 49%) as white crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[OH2:10].[F:11][B-](F)(F)F.F[B-](F)(F)F.O[N+]12CC[N+](F)(CC1)CC2>C(#N)C.CCOCC>[F:11][CH2:3][C:2]([OH:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: F[B-](F)(F)F
Reactant: O
Reactant: C=C(C)c1ccccc1
Agent: O[N+]12CC[N+](F)(CC1)CC2
Solvent: CC#N
Solvent: CCOCC
Product: CC(O)(CF)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
To a solution of alpha-methylstyrene (0.13 mL, 1 mmole) and water (0.02 mL, 1.1 mmole) in acetonitrile (10 mL) was added 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (330 mg, 1.02 mmole 1.02 equ.) and the reaction stirred at room temperature for 24 h. The mixture was diluted with ether (2 mL), filtered through anhydrous MgSO4, and evaporated to afford 110 mg (71% yield) of 1-fluoro-2-hydroxy-2-phenylpropane.
Reaction SMILES: [Cl:1][C:2](=[C:7](Cl)[C:8]([F:11])([F:10])[F:9])[C:3]([F:6])([F:5])[F:4].C1(C)C=CC=CC=1.[CH2:20]([OH:23])[CH2:21][OH:22].[H-].[Na+]>O>[Cl:1][CH:2]([C:7]1([O:23][CH2:20][CH2:21][O:22]1)[C:8]([F:11])([F:10])[F:9])[C:3]([F:6])([F:5])[F:4]
Reactant: OCCO
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)OCCO1
Temperature: 40 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
233 g of 2,3-dichloro-1,1,1,4,4,4-hexafluorobut-2-ene were added dropwise to 400 ml of toluene, 80 g of ethylene glycol and 80 g of 60% strength sodium hydride in mineral oil at room temperature. The reaction mixture was stirred at 40° C. for 5 hours and water was then added. The organic phase was separated off, the aqueous phase was extracted with methyl t-butyl ether and the combined organic phases were dried over sodium sulfate. After removal of the solvent and subsequent distillation in vacuo, 180 g of 2-chloro-1,1,1,4,4,4-hexafluoro-3,3-ethylenedioxybutane (boiling point: 48° C./16 mbar) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[NH:32][CH2:31][N:30]([CH:34]([CH3:36])[CH3:35])[C:29]2=[O:37].N1C=CC=CC=1.C1CN2C(=NCCC2)NC1>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([N:32]2[C:33]3[C:28](=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:23])[C:29](=[O:37])[N:30]([CH:34]([CH3:36])[CH3:35])[CH2:31]2)=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cccc2c1NCN(C(C)C)C2=O
Agent: C1CN=C2NCCCN2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cccc2c1N(C(=O)c1cc(Br)nn1-c1ncccc1Cl)CN(C(C)C)C2=O
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (787 mg, 2.45 mmol) (i.e. the product of Example 1, Step D) in dichloromethane (10 mL) was added dimethylformamide (20 μL) and oxalyl chloride (235 μL). The mixture was stirred for 1 hour, at which point it had become clear. After removing volatiles under reduced pressure, the residue was dissolved in dichloromethane (5 mL) and one half of the solution was added to a mixture of the product of Step A (0.25 g, 1.2 mmol) and pyridine (148 μL, 1.8 mmol) in methylene chloride (10 mL). After stirring at ambient temperature overnight, 1,5,7-triazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (1 g) (Fluka Chemie AG catalog number 90603) was added and the mixture was stirred for an additional 15 minutes. The mixture was then filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel to give the title compound, a compound of the invention, as a white solid (0.18 g).