Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][N:16]=2)[CH2:6][CH2:5]1.[CH3:21][C:22]1([CH3:34])[S:26][C@@H:25]2[C@H:27]([NH2:30])[C:28](=[O:29])[N:24]2[C@H:23]1[C:31]([OH:33])=[O:32].C(N(C(C)C)CC)(C)C.C(Cl)(Cl)[Cl:45]>>[ClH:45].[CH2:17]([N:13]1[CH2:14][CH2:15][N:16]=[C:12]1[CH2:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH:3]=[N:30][CH:27]2[C:28](=[O:29])[N:24]3[CH:25]2[S:26][C:22]([CH3:34])([CH3:21])[CH:23]3[C:31]([OH:33])=[O:32])[CH2:9][CH2:8]1)[CH3:18]
Reactant: ClC(Cl)Cl
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: CCN1CCN=C1CCC1CCN(C(OC)OC)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN=C1CCC1CCN(C=NC2C(=O)N3C2SC(C)(C)C3C(=O)O)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A solution of 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidine (0.66 g, 0.0031M) in methanol (6 ml) and dimethylformamide dimethylacetal (6 ml) was heated at 90° C. for 6 hrs. Removal of the excess of dimethylformamide dimethylacetal gave 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal. The solution of the piperidine carboxaldehyde dimethylacetal in chloroform (5 ml) was then added to a mixture of 6-aminopenicillanic acid (0.6 g, 0.0028M) and diisopropylethylamine (0.5 ml) in chloroform (6 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs. The solvent was removed and water (10 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified from about pH 3 to about 3.5 was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)] -6-[[[4-[2-(1-ethyl-4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.46 g, 35% yield).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.I[CH2:17][CH2:18][CH2:19][CH3:20].CC(C)([O-])C.[K+].O1[CH2:31][CH2:30][CH2:29][CH2:28]1>O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[C:12]2([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: Nc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCCCC1(CCCC)c2cc(N)ccc2-c2ccc(Br)cc21
Temperature: 50 °C

Procedure:
Under N2 atmosphere, 0.52 parts of 7-bromo-9H-fluoren-2-ylamine, 2.21 parts of 1-iodobutane, and 1.35 parts of potassium tert-butoxide were added into 20 parts of dry tetrahydrofuran, followed by stirring and mixing. Then, the reaction mixture was heated to 50° C. and reacted for 18 hours. After the reaction mixture was cooled, water was used for quenching the reaction, diethyl ether was used for extracting the product, and magnesium sulfate was used for dehydration. After removing the solvent, the residual was purified with column chromatography method by using dichloromethane/hexane co-solvent as an eluent, to obtain a compound (31) of the present example. This compound was in a form of a brown-yellow solid, and the yield of this compound was 79%.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol (300 mg, 0.89 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (169 mg, 0.89 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (256 mg, 1.33 mmol) and 1-hydroxy-1H-benzotriazole (136 mg, 0.89 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (148 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 4-chloro-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3): δ 7.20 (dd, 2H, J=4.4 Hz, 2.0), 7.31 (m, 2H), 7.53 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.65 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.79 (dd, 2H, J=4.4 Hz, 1.6 Hz), 10.00 (s, 1H). MS: m/z 407.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].[H][H]>[Pd].C(O)(=O)C>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:11])[N:2]([CH3:1])[C:3]2=[O:15]
Reactant: CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1C(=O)c2cccc(N)c2C1=O
Reaction time: 2 h
Yield: 181.4 %

Procedure:
A pressure reactor was charged with 2-methyl-4-nitro-1H-isoindole-1,3(2H)-dione (59.0 g, 0.286 mol), 1 L acetic acid, and 2 q 5% Pd/C. The reactor was pressurized to 48 psi hydrogen, and the exothermic reaction was complete in 2 hours. The catalyst was removed with hot filtration, and the filtrate combined with the contents of another reactor which contained 53.2 g of 3-nitrophthalimide under the same conditions. The acetic acid was removed at the rotovap, then the salt was cracked by adding 2 M ammonium hydroxide. The slurry was stirred 30 minutes; then filtered; washed with water, ethanol, and ether; and dried at the pump to give 91.4 g, 95% of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C:24]([OH:28])([CH3:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCO.O>[OH:28][C:24]1([CH3:27])[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:23]1
Reactant: CC1(O)CCN(c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC1(O)CCN(c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1
Temperature: 25 °C

Procedure:
3-Bromo-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 11.1, 83 mg, 0.18 mmol), pyrimidin-5-ylboronic acid (66.9 mg, 0.540 mmol) and Na2CO3 (57.2 mg, 0.540 mmol) were added to a MW vial and treated with a mixture of DME (764 μL), water (218 μL) and EtOH (109 μL). The vial was sealed, evacuated/purged with argon and the RM was subjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1 mL) and treated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.9 mg, 0.090 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 20% to 70% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the title compound as a yellow solid. UPLC-MS (condition 1) tR=2.47 min, m/z=459.0 [M+H]+, m/z=457.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 3H) 1.68-1.83 (m, 2H) 2.77 (d, J=9.78 Hz, 1H) 2.87 (d, 1H) 2.97-3.07 (m, 1H) 3.21-3.30 (m, 1H) 4.72 (s, 1H) 6.96 (d, J=9.05 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.80-7.89 (m, 3H) 7.94 (dd, J=8.93, 2.32 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s, 1H), 9.29 ppm.
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:4]>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: II
Reactant: CCc1ccc(OC)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CCc1ccc(OC)c(I)c1
Temperature: 25 °C

Procedure:
A mixture of silver sulfate (1.15 g, 3.68 mmol) and iodine (0.93 g, 3.68 mmol) were stirred in methanol at room temperature. A solution of p-ethylanisole (0.50 g, 3.68 mmol) in methanol was added dropwise to the stirring mixture. The mixture was stirred at room temperature until completion of the reaction. It was filtered and the filtrate was concentrated. The residue was dissolved in methylene chloride, washed with 1 N sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained without further purification. 1H NMR (CDCl3, 500 MHz) δ 7.64 (d, J=2.0 Hz, 1H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 3.88 (s, 3H), 2.58 (q, J=15.5, 8.0 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>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>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)=[N:24][CH:25]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: Fc1ccc(-c2cn[nH]c2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (15.4 g, 52.5 mmol) and 2-bromo-5-fluoropyridine (8.4 g, 47.7 mmol) in 1,4-dioxane (100 mL), Pd(PPh3)4 (5.5 g, 4.77 mmol) and a 2M aqueous solution of Na2CO3 (71.6 mL, 0.14 mol) were added, then the resulting mixture was stirred at 100° C. for 3 hours and then at room temperature for 72 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. A small amount of EtOAc was added to the obtained residue and the resulting mixture was filtered out and dried to obtain the title compound (4.9 g) (colorless solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[CH2:28](O)[CH:29]([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Reactant: CC(C)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)OCC(C)C)CC3)nc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A mixture of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (250 mg, 685 μmol), isobutanol (100 μL, 1.37 mmol), DMAP (250 mg, 2.05 mmol) and EDCI.HCl (262 mg, 1.37 mmol) in DCM (14 mL) was stirred at 50° C. for 2 hours in a sealed vial, before it was diluted with DCM (80 mL), washed with an aqueous 1 M solution of HCl (40 mL) and evaporated to dryness. The crude mixture was redissolved in MeCN (˜2 mL) and the crude product was crystallized upon addition of water (˜2 mL). Column chromatography (gradient EtOAc 20 to 100% in pet. ether) and subsequent recrystallization in MeCN and water afforded the title compound as colorless crystals (178 mg, 62%). HPLC-Retention time (XE Metode 7 CM): 2.34 minutes. Detected “M+1”-mass: 422.16. Calculated “M+1”-mass: 422.17. 1H NMR (DMSO, 600 MHz): δ=8.22 (br s, 1H), 8.13 (dd, 1H, J=8.1 Hz, 1.5 Hz), 8.00 (d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.24 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.04 (s, 3H), 3.84 (d, 2H, J=6.5 Hz), 1.79 (m, 1H), 1.61-1.54 (m, 2H), 1.54-1.46 (m, 2H), 0.78 (d, 6H, J=6.7 Hz) ppm.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33][CH3:34])=[O:32])O1.[C:39](=O)([O-])[O-].[K+].[K+]>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:9]1[CH:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:36]3[CH:37]=[CH:28][CH:29]=[C:30]([C:31]([O:33][CH2:34][CH3:39])=[O:32])[CH:35]=3)[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4]2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1nn(-c2ccc(F)c(F)c2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cccc(-c2cn(-c3ccc(F)c(F)c3)nc2C(=O)OCC)c1
Temperature: 25 °C

Procedure:
180 mg (0.54 mmol) of ethyl 4-bromo-1-(3,4-difluorophenyl)-1H-pyrazole-3-carboxylate, 156.7 mg (0.59 mmol) of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 158 mg (1.14 mmol) of potassium carbonate, 5.07 mg (0.011 mmol) of 2,2-dicyclohexylphosphino-2″,6″-diisopropoxybiphenyl and 1.22 mg (0.005 mmol) of palladium (II)acetate were suspended in 5 ml of ethanol and heated at the boil for 4 h. After cooling to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in water and dichloromethane, the phases were separated and the organic phase was dried over magnesium sulfate. The crude product was purified by chromatography (ethyl acetate:n-heptane 1:4). This gave 84 mg (37%) of the desired product. 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.15 (s, 1H); 8.05 (d, 1H); 7.96 (s, 1H); 7.74-7.69 (m, 2H); 7.53-7.47 (m, 2H); 7.28 (m, 1H); 4.48-4.34 (m, 4H); 1.43 (t, 3H); 1.29 (t, 3H)
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1>COCCOC.O>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][O:5][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CC(C)CCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)CCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 110 °C

Procedure:
To 3-methyl-1-butanol (1.03 mL) in DME (5 mL) was added sodium tert-butoxide (912 mg) in portions over 5 mins with stirring. The mixture was stirred at room temperature until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (600 mg) was added followed by DME (4.6 mL). The reaction was heated at 110° C. overnight. The reaction was allowed to cool, was taken up in water (20 mL) and washed with EtOAc (2×20 mL). The organics were extracted with brine, separated, dried over MgSO4, filtered and concentrated in vacuo to give a viscous yellow oil. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (30-80%) to afford the title compound as a yellow residue (266 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:12]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:10]([CH3:20])=[C:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[N:12]=1
Reactant: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 72.5 %

Procedure:
t-Butyl 2-(2-chlorophenyl)-5-methylimidazole-4-carboxylate (70 mg, 0.24 mmol) was mixed with 4-fluoro-1-nitrobenzene (27 μL, 0.25 mmol) and potassium carbonate (66 mg, 0.48 mmol) in dry DMF and heated at 120° C. for 4 h. The mixture was diluted with water and filtered to give a yellow solid which was chromatographed over silica gel (40% EtOAc in hexane) to afford a yellow solid (72 mg, 73%): 1H NMR (300 MHz, CDCl3) δ 8.20 (m, 2H), 7.51 (m, 1H), 7.25 (m, 5H), 2.45 (s, 3H), 1.66 (s, 9H).
Reaction SMILES: [CH:1]1([NH:6][C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]([C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC1
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCCC1)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](N(C1CCCC1)C1CCC1)CO2
Reaction time: 144 h
Yield: 48.8 %

Procedure:
To a solution of (R)-3-(N-cyclopentylamino)-8-fluoro-5- methoxy-3,4-dihydro-2H-1-benzopyran (0.9 g, 3.4 mmol), HOAc (0.22 g, 3.6 mmol) and cyclobutanone (2g, 30 mmol) in methanol (25 mL), were NaCNBH3 (1 g, 16 mmol) added in portions at room temperature. After stirring for four days GC indicated 37% product. pH was adjusted to 5 (HOAc)and additional (1 g, 15 mmol) cyclobutanone was added. After stirring for further 6 days, GC indicated 64% conversion. The solvent was evaporated and the residue worked up by extraction. Flash chromatography (EtOAc/P-ether, 1+1), gave 0.53 g (53% yield) of the title compound as a colourless oil. GC/MS (70 eV) M=319 (3%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[I:27])[CH3:18].[CH2:28](OC(OCC)OCC)C>C(O)(C)C>[C:1]([C:3](=[CH:28][NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:17][CH3:18])=[C:21]([I:27])[CH:22]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Reactant: CCOc1ccc(N)cc1I
Solvent: CC(C)O
Product: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1I
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (5.44 g, 21.0 mmol) in 350 mL of iso-propanol, under N2, was added (4-ethoxy-3-iodophenyl)amine (5.0 g, 19.30 mmol). This mixture was heated to reflux and triethylorthoformate (8.53 mL, 51.30 mmol) was added dropwise and the reaction mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature and the yellow solid was collected by filtration, washed with iso-propanol, and dried overnight at ˜40° C. under reduced pressure to give 5.46 g (54%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-iodophenyl)amino]prop-2-enamide as a yellow solid, mp >245° C.; MS (EI) m/z 531.01 (M)+
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][C:6]([CH3:10])([CH3:9])[CH:7]=[O:8].C(N(CC)CC)C>CCOC(C)=O>[CH3:5][C:6]([CH3:10])([CH3:9])[CH:7]([OH:8])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.3 %

Procedure:
A mixture of nitromethane (5.87 g, 68.1 mmol), 2,2-dimethyl-propionaldehyde (5.4 g, 88.6 mmol), and triethylamine (689 mg, 6.8 mmol) was stirred at room temperature for two days; then the reaction mixture was diluted with EtOAc, washed with diluted HCl aqueous solution, and saturated NaCl aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a clear oil, the title product (7.35 g); The title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=4.52 (dd, 1H, J=2.4 Hz, 12.6 Hz), 4.36 (dd, 1H, J=10.0 Hz, 12.6 Hz), 4.01 (m, 1H), 2.42 (d, 1H, J=4.4 Hz), 0.98 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:28]1[CH:32]=[CH:31][CH2:30][CH2:29]1.C(=O)([O-])O.[Na+]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH:29]4[CH2:30][CH2:31][CH2:32][O:28]4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C1=COCC1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CCCO1
Yield: 80.8 %

Procedure:
In a solution of 1.25 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19 and 0.32 g of 2,3-dihydrofuran in 30 mL of dichloromethane, 0.01 g of p-toluene sulfonic acid monohydrate was added at room temperature with stirring, and stirred at room temperature for 3 days. After the completion of the reaction, 30 mL of saturated sodium hydrogen carbonate aqueous solution was added in the reaction mixture, extracted with ethyl acetate (30 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 1.18 g of the aimed product as colorless resinous substance.
Reaction SMILES: [F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH2:17][NH2:18]>>[F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3]([NH:17][NH2:18])=[O:4]
Reactant: NN
Reactant: CCOC(=O)C(F)(F)C(O)c1ccncc1
Product: NNC(=O)C(F)(F)C(O)c1ccncc1

Procedure:
α,α-difluoro-β-hydroxy-3-(4-pyridinyl)-propanoic acid, hydrazide (50) was prepared in the manner described in Example 10 on a 20 mmol scale using ethyl α,α-difluoro-β-hydroxy-3-(4-pyridinyl)-propanoate and hydrazine to yield 2.7 g (62%) of product. This product was used immediately in the manner described in Example 51, below.