Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.[OH:14][CH:15]([C:21]([CH3:23])=[CH2:22])[C:16]([O:18]CC)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:18])[C:15](=[C:21]([CH3:22])[CH3:23])[O:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CCOC(=O)Nc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 40.5 %

Procedure:
Ethyl N-(4-chlorophenyl)carbamate (2.02 g, 10.1 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (2.97 g, 22.8 mmol) and tetrabutylammonium bromide (243 mg, 1.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 3.5 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, a mixed solvent consisting of methanol (5 mL) and 6N hydrochloric acid (0.25 mL) was added. The precipitated solid was collected by filtration, then washed with a 10:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chlorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.03 g, yield 40.5%).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].N>C(O)C.CO.[OH-].[Pd+2].[OH-]>[C:13]1([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[CH2:19][OH:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Agent: [Pd+2]
Agent: N
Agent: O=C[O-]
Solvent: CO
Solvent: CCO
Product: OC[C@H]1CNC[C@@H]1c1ccccc1
Yield: 82.6 %

Procedure:
To ((3R,4S)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methanol (2.28 g, 8.54 mmol) in ethanol (200 mL) was added ammonium formate (5.39 g, 85.49 mmol) and palladium hydroxide (446 mg, 20 wt % Pd) and refluxed for 1.5 h. Ammonia in methanol (0.8 mL, 2M) was added to the reaction mixture and refluxed for an additional 0.5 h. The reaction mixture was filtered through celite and concentrated to give ((3R,4S)-4-phenyl-pyrrolidin-3-yl)-methanol as a colorless oil (1.25 g) which was used directly in the next step.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[CH:6]=1)[CH3:3].[CH2:17]([OH:19])[CH3:18]>>[ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9](=[NH:10])[O:19][CH2:17][CH3:18])=[C:7]([O:13][CH:14]([CH3:15])[CH3:16])[CH:6]=1)[CH3:3]
Reactant: CCOc1ccc(C#N)c(OC(C)C)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OCC)cc1OC(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Hydrogen chloride gas was passed through a solution of 4-ethoxy-2-isopropoxy-benzonitrile (0.30 g, 1.46 mmol) in absolute ethanol (100 mL) in a pressure tube for 45 min at 0° C. The tube was sealed and stirred at room temperature for 4 d. The pressure was released only after the tube is cooled to 0° C. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 4-ethoxy-2-isopropoxy-benzimidate hydrochloride which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[C:8](N)=[CH:7][CH:6]=1)=[O:4].Cl.N([O-])=O.[Na+].[I-:22].[K+]>C1COCC1.O.CCOC(C)=O>[OH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=[C:8]2[I:22]
Reactant: [I-]
Reactant: COC(=O)c1ccc(N)c2cc(O)ccc12
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(I)c2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl-4-amino-6-hydroxy-1-naphthoate (0.500 g, 2.30 mmol) in THF (2.5 mL) was cooled to 0° C. and 3 N HCl (5.0 mL) was added. A solution of sodium nitrite (0.175 g, 2.53 mmol) in water (1.2 mL) was added and the mixture stirred at 0° C. for 15 min. A solution of potassium iodide (0.764 g, 4.60 mmol) in water (1.2 ml) was added and the mixture was stirred at 0° C. for 1 h. EtOAc was added and the solution was poured into water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a red-brown oil. This material was purified via column chromatography on silica gel (eluting with 0-50% EtOAc-hexane) to afford methyl 6-hydroxy-4-iodo-1-naphthoate as a tan solid. MS (ESI, pos. ion) m/z: 328.8 (M+H). Mass Calc'd for C12H9IO3: 328.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:24]C)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:10]=2)[CH:8]=1)#[N:2].[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28].C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[NH2:16][CH2:15][C:11]1[CH:10]=[C:9]([C:7]2[C:6]([OH:24])=[CH:5][CH:4]=[C:3]([C:1]3[NH:2][N:28]=[N:27][N:26]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccc(C#N)cc1-c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
tert-Butyl (5′-cyano-2′-methoxy-biphenyl-3-yl-methyl)-carbamate (0.73 g, 2.16 mmol), prepared as in Reference 19, and azidotributyltin (0.9 mL, 3.2 mmol) was dissolved in toluene (5 mL) and the solution was refluxed for 14 hours. The mixture cooled to room temperature and then workup with ethyl acetate and 1N HCl gave a slurry. The slurry was dried by rotovap and then triturated with hexanes. The solids were collected by filtration and treated with hydrobromic acid (48% aqueous, 15 mL). The mixture was refluxed for 14 hours at 120° C. and then diluted with water (50 mL). The dilution was dried by lyophilization to give 3′-aminomethyl-5-(1H-tetrazol-5-yl)-biphenyl-2-ol (0.4 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:21])[NH:13][C@@H:14]([C:16](=O)[N:17]([CH3:19])[CH3:18])[CH3:15])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([O:11][C:12](=[O:21])[NH:13][C@H:14]([CH3:15])[CH2:16][N:17]([CH3:18])[CH3:19])([CH3:10])([CH3:9])[CH3:8]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H](CN(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 90.9 %

Procedure:
Reduction was carried out according to Chem. Eur. J. (2008), 14(17), 51116-5119. To an ice-cooled lithium aluminum hydride (in Et2O) (21.35 mL, 21.35 mmol) solution was added drop wise a solution of ((R)-1-dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester (1.7105 g, 7.12 mmol) in Et2O (2-3 mL). The reaction mixture was stirred at 0° C. until disappearance of the starting material. The reaction mixture was carefully quenched by sequential addition of water (1.2 mL), 15% (w/w) NaOH (1.2 mL) and water (3.6 mL). Then EtOAc was added and the solids were filtered and washed with EtOAc. The filtrated was dried over MgSO4, filtered and evaporated off. Then the crude was dissolved in DCM, filtered and evaporated off to give 1.4543 g, 6.47 mmol, 91% yield ((R)-2-Dimethylamino-1-methyl-ethyl)-carbamic acid tert-butyl ester as yellowish oil. The crude was used without any further purification and characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:16](=[O:21])[CH2:17][CH2:18][C:19]#[C:20][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccn1
Agent: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1cccc(Cl)c1

Procedure:
The title compound was prepared in accordance with the general method of Example 244(C), from tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate (250 mg, 0.82 mmol) and 2-bromopyridine (129 mg, 0.82 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column cyclohexane/AcOEt:70/30 as eluent) to afford 226 mg of tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate as a brown oil (Yield: 72%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][N:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:32][CH:31]([F:33])[O:30][C:27]1[CH:28]=[CH:29][C:24]([NH:1][C@H:2]2[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]2[NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[N:25][CH:26]=1
Reactant: N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)Oc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CC(F)(F)C[C@@H]1Nc1ccc(OC(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 110 °C

Procedure:
To a solution of N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 46; 100 mg, 0.33 mmol) in dry toluene (3 ml) was added 2-bromo-5-(difluoromethoxy)pyridine (CAS number 845827-14-7; 89 mg, 0.33 mmol), BINAP (20 mg, 0.033 mmol), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.016 mmol) and sodium tert-butoxide (44 mg, 0.46 mmol). The reaction was placed under an atmosphere of nitrogen, sealed and heated at 110° C. for 2.5 hours then filtered through a thiol cartridge, eluting with ethyl acetate and water. The filtrate was diluted with further ethyl acetate and water and then partitioned. The organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) then triturated with heptane and diethyl ether to afford the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][C:10]1([C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[CH2:27][CH2:28]OS(C(F)(F)F)(=O)=O)(=O)=O>O1CCCC1>[C:3]([O:7][C:8]([N:9]1[CH2:28][CH2:27][N:14]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:13](=[O:19])[C:10]21[CH2:12][CH2:11]2)=[O:20])([CH3:6])([CH3:4])[CH3:5]
Reactant: C=CCCNC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(OCCOS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCN1CCN(C(=O)OC(C)(C)C)C2(CC2)C1=O
Reaction time: 1 h
Yield: 47.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 206 mg, 5.15 mmol) was added at 0° C. to a solution of (1-but-3-enylcarbamoyl-cyclopropyl)-carbamic acid tert-butyl ester (400 mg, 1.57 mmol) in tetrahydrofuran (8 ml), then after 15 min a solution of 1,2-bis(((trifluoromethyl)sulfonyl)oxy)ethane (Chem. Ber. 1981, 114, 810; 616 mg, 1.89 mmol) in tetrahydrofuran (1 ml) was added dropwise. After 1 h, another portion of sodium hydride (60% dispersion in mineral oil, 103 mg, 2.58 mmol) and after 15 min, 1,2-bis(((trifluoromethyl)sulfonyl)oxy)ethane (616 mg, 1.78 mmol) was added, and die reaction mixture was allowed to reach room temperature over 1 h, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (208 mg, 47%). Yellow oil, MS (ISP)=281.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[C:16]1([C:3]2[C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:31])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: Cc1ccccc1-c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Yield: 86.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and o-tolylboronic acid (78.9 mg, 0.58 mmol, 2.00 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 85 mg (84%) of 2-phenyl-3-o-tolylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[C:12]1[C:13](=[O:32])[N:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:15]=[C:16]([C:19]2([CH3:24])[O:23][CH2:22][CH2:21][O:20]2)[C:17]=1[CH3:18].O>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:14]2[C:13](=[O:32])[C:12]([O:10][CH2:9][C:5]3[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=3)=[C:17]([CH3:18])[C:16]([C:19]3([CH3:24])[O:23][CH2:22][CH2:21][O:20]3)=[N:15]2)=[CH:30][CH:29]=1
Reactant: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1Br
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 62.5% sodium hydride (92 mg) in N,N-dimethylformamide (8 ml) was added 3-pyridylcarbinol (0.25 ml) under ice cooling, followed by stirring at room temperature for 20 minutes. Then, 4-bromo-2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-3(2H)-pyridazinone (738 mg) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was crystallized from ether to obtain 2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-4-(3-pyridylmethoxy)-3(2H)-pyridazinone (320 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.[Cu]Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][C:25]=3[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:14]=2)=[CH:8][C:7]=1[CH3:20]
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3)c2)cc1C
Temperature: 120 °C
Yield: 33.2 %

Procedure:
A mixture of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.474 g, 1.36 mmol), 4-chloro-2-phenoxy-phenol (0.30 g, 1.36 mmol), cesium carbonate (0.531 g, 1.63 mmol), copper (I) chloride (0.067 g, 0.677 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (0.063 g, 0.342 mmol) in 1-methyl-2-pyrrolidinone (5 mL) is heated to 120° C. for 20 hours under N2. The reaction is cooled and quenched with 1 N HCl (20 mL). The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 0.221 g (33%) of the title compound. Rf=0.29 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H25O5Cl 488, found 489 and 351 (M+1 and M+3, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][N:9]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][N:9]=[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=2)[CH2:26][CH2:25]1
Reactant: Clc1cc(NN=C(c2ccccc2)c2ccccc2)ncn1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN1CCN(c2cc(NN=C(c3ccccc3)c3ccccc3)ncn2)CC1
Temperature: 120 °C

Procedure:
500 mg (1.62 mmol) of the compound from Example 4A, 178 mg (1.78 mmol) of N-methylpiperazine, 58 mg (0.12 mmol) of dicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine, 22 mg (24 μmol) of tris(dibenzylideneacetone)dipalladium and 1.32 g (4.05 mmol) of cesium carbonate are combined. The mixture is degassed and vented twice with argon, 12.5 ml of a mixture of tert-butanol and toluene (1:5) are added, the mixture is again degassed and vented twice with argon and heated at 120° C. for 24 h. Another 58 mg (0.12 mmol) of dicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine and 22 mg (24 μmol) of tris(dibenzylideneacetone)dipalladium are then added, the mixture is heated at 120° C. overnight, another 324 mg (3.24 mmol) of N-methylpiperazine are then added and the mixture is heated at 120° C. for a further night. After cooling, the reaction mixture is filtered through kieselguhr, the filtrate is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32](F)=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])(=[O:28])=[O:27])[CH2:23][N:22]2[C:40]2[N:41]([CH:46]3[CH2:49][CH2:48][CH2:47]3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14]>CN(C=O)C>[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][C:30]=3[C:36]([F:37])([F:39])[F:38])(=[O:27])=[O:28])[CH2:23][N:22]2[C:40]2[N:41]([CH:46]3[CH2:49][CH2:48][CH2:47]3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
2,2,2,-Trifluoroethanol (10 ul, 137 umol; CAS Reg. No. 75-89-8 99) and cesium carbonate (45 mg, 137 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (37 mg, 69 umol; example 388 g) in DMF (500 ul) under an argon atmosphere. The reaction mixture was stirred for 72 h at ambient temperature and partitioned between ice water/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was extracted one more time with iPrOAc. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give a yellow foam which was purified by preparative chiral HPLC to give the title compound (13 mg, 21 umol; 31%) as colorless foam. MS (ESI): m/z=620.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(CC)CC>CCO>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([NH2:12])[N:3]=2)[CH2:16][CH2:15]1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2nc(N)nc3c2CCCC3)CC1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of 4-chloro-5,6,7,8-tetrahydro-quinazolin-2-ylamine (100 mg, 0.55 mmol), N-methyl piperazine (91 uL, 1.5 mmol) and Et3N (140 uL, 1.1 mmol) in EtOH (2 ml) was heated at 70° C. for 16 h. The mixture was cooled to rt and concentrated, and the crude residue was purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (31 mg, 23%). MS (ESI): mass calcd. for C13H21N5, 247.3; m/z found, 248.2 [M+H]+. 1H NMR (MeOD): 3.30-3.23 (m, 4H), 3.21 (dt, J=3.3, 1.6, 1H), 2.49 (t, J=6.7, 2H), 2.47-2.41 (m, 4H), 2.36 (t, J=5.9, 2H), 2.23 (s, 3H), 1.77-1.67 (m, 2H), 1.62-1.52 (m, 2H).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([S:39]([C:42]2([CH3:50])[CH:47]=[C:46]([CH3:48])[CH:45]=[C:44]([CH3:49])[CH2:43]2)(=[O:41])=[O:40])[CH2:35][CH2:34]1>>[F:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:34][CH2:35][N:36]([S:39]([C:42]2([CH3:50])[CH:43]=[C:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[CH2:47]2)(=[O:41])=[O:40])[CH2:37][CH2:38]1
Reactant: COc1cc(F)c(N2CCN(S(=O)(=O)C3(C)C=C(C)C=C(C)C3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: CC1=CC(C)(S(=O)(=O)N2CCN(c3cc(F)c(O)cc3F)CC2)CC(C)=C1
Yield: 52.1 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 4-(2,5-difluoro-4-methoxyphenyl)-1-(1,3,5-trimethylphenylsulfonyl)-piperazine (268 mg). The resulting crude product was purified on TLC (developer, hexane: ethyl acetate=2:1) to provide 4-(2,5-difluoro-4-hydroxyphenyl)-1-(1,3,5-trimethylphenylsulfonyl)-piperazine (135 mg).
Reaction SMILES: [C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.CS(Cl)(=O)=O.CS(O[C@@H]1[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O[C@H]1N1C=CC(=O)NC1=O)(=O)=O.C([O-])(=O)C1C=CC=CC=1.[Na+].Br.C(Br)(=O)C.[C:67]([O:75][CH2:76][C@H:77]1[O:81][C@@H:80]([N:82]2[CH:89]=[CH:88][C:86](=[O:87])[NH:85][C:83]2=[O:84])[C@H:79](Br)[C@@H:78]1OS(C)(=O)=O)(=[O:74])[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>N1C=CC=CC=1.C(N)(=O)C.CN(C)C=O.[Ni].C(O)C.[C].[Pd]>[C:67]([O:75][CH2:76][C@H:77]1[O:81][C@@H:80]([N:82]2[CH:89]=[CH:88][C:86](=[O:87])[NH:85][C:83]2=[O:84])[CH2:79][CH2:78]1)(=[O:74])[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: CS(=O)(=O)O[C@H]1[C@@H](Br)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1
Agent: [Ni]
Agent: [Pd]
Agent: Br
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(OC[C@@H]1CC[C@H](n2ccc(=O)[nH]c2=O)O1)c1ccccc1
Yield: 60 %

Procedure:
Moreover, 2',3'-dideoxy-uridine or the derivatives thereof being the raw materials can be obtained easily from uridine being a constituting ingredient of ribonucleic acid by known method. For example, in the method described in Chem. Pharm. Bull., 18(3), 554-560, 1970, uridine is treated with methanesulfonyl chloride in pyridine solvent to convert to 2',3',5'-tri-O-methanesulfonyluridine and, by allowing this to react with sodium benzoate in acetamide or dimethylformamide solvent, 2,2'-anhydro-1-(5'-O-benzoyl-3'-O-mesyl-β-arabinosyl)uracil is obtained. This is allowed to react with hydrogen bromide or acetyl bromide to convert to 5'-O-benzoyl-2'-bromo-2'-deoxy-3'-O-mesyluridine and then this is treated with palladium carbon or Raney nickel catalyst in ethanol under atmosphere of hydrogen to obtain 5'-O-benzoyl-2',3'-dideoxy-uridine in a yield of about 60% (Chem. Pharm. Bull., 18(3), 554-560, 1970).