Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:9]1[CH:10]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:11][CH2:12][CH2:13][CH:8]1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Clc1cccnc1C1CCCC(c2ncccc2Cl)N1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2Cl)CCCC1c1ncccc1Cl
Yield: 82.3 %

Procedure:
Using General Procedure A: 3,3″-dichloro-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (304 mg, 0.987 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (351 mg, 1.38 mmol), KI (32.7 mg, 0.197 mmol), DIPEA (0.34 mL, 1.97 mmol), and DMF (5 mL) were stirred at 60° C. for 3 h. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH, 98:2) afforded 5-cyano-2-(3,3″-dichloro-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (391 mg, 82%) as a yellow oil. 1H NMR (CDCl3) δ 1.63-1.78 (m, 3H), 2.01-2.14 (m, 1H), 2.18-2.38 (m, 2H), 3.87 (s, 3H), 3.95 (s, 2H), 4.52 (dd, 2H, J=11.4, 1.6 Hz), 6.89 (dd, 2H, J=8.4, 4.9 Hz), 7.38-7.48 (m, 3H), 7.57 (d, 1H, J=1.7 Hz), 8.22-8.32 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.O.[Cl-].[NH4+:14].[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:14]2[C:6]3[CH:7]=[CH:2][CH:3]=[CH:4][C:21]=3[C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: [NH4+]
Reactant: Cc1ccccc1
Agent: [Cl-]
Solvent: O
Product: FC(F)(F)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
The reaction was conducted for 15 minutes in the same experimental procedures as in Example 1 except for using 4-chlorobenzotrifluoride (8.4 mL, 63.1 mmol, 1.0 equivalent) as an aryl halide. After cooling the reaction mixture to room temperature, to the mixture were added water (25 mL) and ammonium chloride (1.7 g). The aqueous layer was separated off, and the organic layer was concentrated under reduced pressure to give solid residue. The residue was dissolved in toluene, and the solution was decolorized by silica gel (1 g) and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the solid, which was recrystallized from toluene/methanol to afford 18.4 g of N-(4-trifluoromethylphenyl)carbazole as a white powder.
Reaction SMILES: B(Cl)(Cl)Cl.[NH:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:19](#N)[CH3:20].Cl.[OH2:23]>ClC(Cl)C>[C:19]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:5][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)(=[O:23])[CH3:20]
Reactant: O
Reactant: CC#N
Reactant: CN1CCC(Nc2ccccc2)CC1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccccc1NC1CCN(C)CC1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a 2.03M solution of boron trichloride (20×1.2 mmol) in dichloroethane (11.8 ml) is dropwise added a solution of 4-anilino-1-methylpiperidine (3.81 g, 20 mmol) in dichloroethane (38 ml), and acetonitrile (2.1 ml, 20×1.2 mmol) is added to the mixture, which is heated under reflux over a period of 20 hours. After cooling, the reaction mixture is mixed with 2N hydrochloric acid (15 ml) and water (30 ml) and stirred at 100° C. over a period of 20 minutes. After cooling, the reaction mixture is mixed with conc. aqueous ammoniac solution and separated. The organic layer is washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo to give 4-(2-acetylanilino)-1-methylpiperidine (4.41 g) as an oil. The yield is 95%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].CNC.[SH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17]C(OCC)=O)[N:16]=1>O1CCCC1.C(OCC)(=O)C.O>[CH3:3][N:4]([CH3:7])[C:5](=[O:6])[CH2:17][C:15]1[N:16]=[C:12]([SH:11])[S:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1csc(S)n1
Agent: CNC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)Cc1csc(S)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium hydride (24 mg) and N,N-dimethylformamide (4.0 ml) was added a solution of dimethylamine (54 mg) in tetrahydrofuran (320 μl) at -10° C. After stirring at room temperature for 1 hour, ethyl 2-mercapto-4-thiazole acetate (203 mg) was added to the mixture at room temperature. After stirring at room temperature for 3 hours, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate) to give N,N-dimethyl-2-mercapto-4-thiazole acetamide (72 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[ClH:29].O1CCOCC1>CO>[ClH:29].[NH:20]1[CH2:21][CH:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:19]1
Reactant: Cn1cc(Br)cc(Nc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(OC3CNC3)cn2)c1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 199d (1.46 g, 3.2 mmol) and HCl/1,4-dioxane (3.2 mL, 12.8 mmol, 4 M) in methanol (20 mL) was heated at 80° C. for 1 h. The mixture was concentrated under reduced pressure to give 199e (1.24 g, 99%). MS: [M+H]+ 351.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[N:11]([CH3:13])[CH3:12])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]([N:10]([C:9]1[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])[N:11]([CH3:13])[CH3:12])=[O:23]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)N(C(=O)c1ccc(Cl)cc1Cl)c1cc(-c2ccccc2)sc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.11 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 10 mL) and then added 1N aqueous solution of LiOH.H20 (0.67 mL, 0.67 mmol). The reaction mixture was stirred at 60° C. for 2 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by preparative TLC using dichloromethane:methanol (9:1) to obtain 3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid (Compound 72) (0.008 g, 17%). 1H NMR (DMSO, 400 MHz): δ 7.81 (d, 2H), 7.69 (d, 2H), 7.54-7.40 (m, 5H), 2.42 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([O:30][Si](C)(C)C)=[CH:28][CH3:29]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:28]([CH3:29])[C:27]([O:26][CH3:25])=[O:30])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CC=C(OC)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
(a)(b) To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (800 mg, 2.5 mmol) and (1-methoxyprop-1-enyloxy)trimethylsilane (1 mL, 6.25 mmol) in 30 mL of dry DCM was added TiCl4 (2.5 mL of 1.0 M DCM solution, 2.5 mmol) and then stirred 1 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, concentrated to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoat. Crude methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoate was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 770 mg (82% yield, 2 steps) of acid 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid. MS found: (M+H)+=375.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCCC2=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCN1C1CNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A mixture of 3-(2-oxopyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (320 mg, 1.33 mmol) and TFA (1.5 mL) in DCM (3 mL) was stirred at room temperature for 4 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Azetidin-3-ylpyrrolidin-2-one as a white solid (174 mg, 93%). 1H NMR (CDCl3, 300 MHz): γ 5.05 (m, 1H), 3.85-3.76 (m, 4H), 3.61 (m, 2H), 2.41 (m, 2H) and 2.07 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][CH2:16][C:13]32[CH2:15][CH2:14]3)=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>O1CCOCC1>[CH2:15]1[C:13]2([CH2:16][CH2:17][CH2:18][CH2:19][N:12]2[C:10]2[N:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]3=[N:8][N:9]=2)[CH2:14]1
Reactant: O=C(NNc1ccc(F)cn1)N1CCCCC12CC2
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Fc1ccc2nnc(N3CCCCC34CC4)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of Intermediate 148b (587 mg, 2.22 mmol), triphenyl phosphine (1.17 g, 4.44 mmol) and triethylamine (1.24 mL, 8.88 mmol) in dioxane (25 mL) at RT was added hexachloroethane (1.05 g, 4.44 mmol). The resulting opaque solution was stirred at RT for 30 min, and at reflux for 16 h. The cooled solution was filtered, and the filter-cake washed with THF (5 mL). The combined organics were applied to an SCX-2 cartridge, which was washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a brown oil. Flash chromatography (silica 40 g, 1.5-4.5% MeOH in DCM) gave the title compound as a brown gum (82%). LCMS (Method 3): Rt 2.92 min, m/z 247 [MH+].
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH3:14][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2c(C=O)cccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.6 %

Procedure:
To a solution of 1H-indole-4-carbaldehyde (413 mg, 2.85 mmol) in anhydrous DMF (6.5 mL) was added sodium hydride (171 mg of 60% dispersion in oil, 4.27 mmol). The mixture was stirred for 40 min at room temperature. Methyl iodide (0.36 mL, 5.78 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (25 mL) and the mixture was extracted with ethyl acetate (3×25 mL). Combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to a yellow oil. Purification by column chromatography (silica gel, CH2Cl2) gave 1-methyl-1H-indole-4-carbaldehyde (452 mg g, 99%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.38-7.34 (m, 1H), 7.08 (d, J=3.2 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CN(C)C=O.Cl.[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[CH2:11][CH2:10][N:9]2[C:32]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:24]([CH3:37])[CH3:23])=[CH:36][CH:35]=2)=[O:33])=[CH:6][CH:7]=1
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Reactant: Clc1ccc(C2NCCc3sccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccc(C(=O)N2CCc3sccc3C2c2ccc(Cl)cc2)cc1

Procedure:
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 ul), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[F:12].C(NC(C)C)(C)C.[Li].CN(C)[CH:23]=[O:24].C(O)(=O)C>O1CCCC1>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([O:8][CH:9]([CH3:10])[CH3:11])[C:4]=1[CH:23]=[O:24]
Reactant: CC(C)Oc1ccc(F)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)Oc1ccc(F)c(F)c1C=O
Yield: 89.8 %

Procedure:
In a manner similar to the method described in example 52a, 1,2-difluoro-4-isopropoxy-benzene (5.77 g, 33.5 mmol) prepared in example 62a was reacted with lithium diisopropyl amine (20.5 mL, 1.8 M in THF, 36.9 mmol), N,N-dimethyl-formamide (3.11 mL, 40.2 mmol) and quenched with acetic acid (8.0 g, 134 mmol) in tetrahydrofuran to give 2,3-difluoro-6-isopropoxy-benzaldehyde as a white crystal (Yield: 6.02 g, 89.9%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>O.C(OCC)C>[CH2:1]([NH:4][C:16](=[O:17])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5](=[O:7])[CH3:6])=[CH:14][CH:13]=1)[CH2:2][CH3:3]
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Reactant: CCCN
Solvent: CCOCC
Solvent: O
Product: CCCNC(=O)Cc1ccc(OC(C)=O)cc1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 1-propylamine (9 g) in water (50 ml) was added solution of 4-acetoxyphenylacetyl chloride (10.6 g) in diethyl ether (100 ml), keeping the temperature of the mixture between 15° and 25° C. with external cooling. The ether layer was separated, washed with brine and evaporated to give N-(1-propyl)-4-acetoxyphenylacetamide as a pale yellow oil, essentially pure by TLC, which was used without further purification or characterisation.
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(=O)([O-])O.[Na+].[CH2:23]([O:30][C:31](Cl)=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(Cl)Cl.C(#N)C>CC(N(C)C)=O>[CH2:23]([O:30][C:31]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reactant: CCCCCCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 4.15 g of sodium hydrogen carbonate and 4.41 g of heptylchloroformate. The resultant mixture is allowed to react under stirring at room temperature for 3 hours. After the reaction, dimethylacetamide is removed under reduced pressure and 150 ml of cold water is added to the residue. After the mixture is stirred for 2 hours, the solids are collected by filtration and dried. Recrystallization of the white powders obtained is performed twice, using 200 ml and 150 ml of a mixture of chloroform-acetonitrile (1:1), to give 2.5 g of N4 -heptyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:40%).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([O-:16])=[O:15]>CN(C)C=O.C(Cl)(Cl)Cl>[N+:14]([C:17]1[N:18]=[CH:19][N:20]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[OH:7])[CH:21]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: C1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cn(C2CCCCC2O)cn1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
40.0 ml (395 mmol) of cyclohexene oxide and 86.37 g (625 mmol) of potassium carbonate were added to a suspension of 50.08 g (443 mmol) of 4-nitroimidazole in 800 ml of N,N-dimethylformamide. The obtained mixture was stirred under heating at 100° C. for 3 days and 20 hours to give a yellowish-brown suspension. This suspension was cooled by allowing to stand, and filtered to remove insolubles. The filtrate was concentrated in a vacuum. Water was added to the obtained residue to form a crystalline precipitate. This crystalline precipitate was recovered by filtration and washed with water. The obtained crude crystal was dissolved in chloroform and the obtained solution was washed with a saturated aqueous solution of common salt. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum. In the course of the concentration, a crystal began to precipitate. This crystal was recovered by filtration to give 53.26 g of the title compound as a colorless crystal. Further, the filtrate was recrystallized from dichloromethane/diisopropyl ether to give 5.14 g of the title compound as a light-brown crystal. Thus, 58.30 g of the title compound was obtained in total (yield: 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[C:38]([CH3:44])=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=1>>[CH3:44][C:38]1[C:37]([C:20]2[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:22][CH:21]=2)=[CH:42][CH:41]=[C:40]([CH3:43])[N:39]=1
Reactant: Cc1ccc(Br)c(C)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c(C)n1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-bromo-2,6-dimethylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.012, m/z=463.1; 1H NMR (CDCl3) 1.32 (m, 2H), 1.49 (d, 3H), 1.62 (m, 2H), 1.86-1.96 (m, 2H), 2.17-2.29 (m, 3H), 2.31 (s, 3H), 2.49 (s, 3H), 2.93 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.88-7.03 (m, 7H), 7.25 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33].O>CC#N.CN(C)C1C=CN=CC=1>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[CH:27][C:26]=1[O:25][CH3:24]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)cc1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (50 mg) was dissolved in CH3CN (2 mL). To this solution was added 3-methoxy-4-methoxycarbonyl-phenylboronic acid pinacol ester (120 mg, [CAS Reg. No. 603122-40-3]), cupric(II)-acetate (74.5 mg) and 4-dimethylaminopyridine (66.7 mg). The rection mixture was stirred at 80° C. for 18 hours. The mixture was cooled, poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by amino phase chromatography (ethyl acetate:heptane=2:3) to give the desired compound as a colorless solid (24 mg, 33%). MS (neg. ion, m/e)=527.9 [(M−H)−].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[NH:8][O:9][C:5]=2[CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[CH3:18][O:17][C:15](=[O:16])[CH2:14][N:8]1[C:7](=[O:10])[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9]1
Reactant: COC(=O)CBr
Reactant: COc1ccc2c(=O)[nH]oc2c1
Solvent: C1CCOC1
Product: COC(=O)Cn1oc2cc(OC)ccc2c1=O
Yield: 43.5 %

Procedure:
The KN(TMS)2 (7.2 g) was added to a solution of compound 22B (4 g) in 150 mL of THF at 0° C. by portion, another one hour at 0° C. with stirring. Methyl bromoacetate (7 g) was added, stirred at RT overnight. The reaction mixture was quenched with 150 mL of ethyl acetate and 100 mL of 2N HCl. The organic layer was separated, washed with water, brine, dried (MgSO4), concentrated to afford an off-white solid compound 22C (2.5 g). mp 185-188° C.; MS: 238 (M+1)+. Preparation of 5-Chlorosulfonyl-6-methoxy-3-oxo-3H-benzo[d]isoxazol-2-yl-acetic acid methyl ester (Compound 22D)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[CH2:37]([NH2:40])[C:38]#[CH:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28]([NH:40][CH2:37][C:38]#[CH:39])=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: C#CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C#CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy)-aniline (50 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (45 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propargylamine hydrochloride (21 mg) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. The precipitated crystal was collected by filtration and was washed to give 38 mg (yield 61%) of the title compound.