Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[N:15]1([CH2:14][CH2:13][NH:12][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Fc1ncccc1C(F)(F)F
Reactant: NCCN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cccnc1NCCN1CCCC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To the solution of 2-fluoro-3-(trifluoromethyl)pyridine (990 mg, 6 mmole) in 5 ml of NMP, 2-aminoethylpyrrolidine (1.13 ml, 9 mmole) and triethylamine (1 ml, 7.2 mmole) were added. The reaction solution was stirred at 85° C. for overnight. The reaction mixture was poured into 40 ml of saturated NaHCO3 and extracted with ethyl acetate (2×80 ml). The combined organic layers were washed with water (2×30 ml) and brine (30 ml), then dried over Na2SO4 and evaporated in vacuo to give a brown oily N-(2-(pyrrolidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2-amine (1.61 g). ES/MS m/z 260.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=3)[CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:43].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:16]2[CH:21]=[C:20]([CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:43])=[O:30])=[CH:25][CH:24]=2)=[O:40])[CH2:10][CH2:9]1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C=O)cc3)c2)CC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C(=O)O)cc3)c2)CC1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
0.5 g (0.9 mmol) of {4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoyl-amino]-cyclohexyl}-carbamic acid tert-butyl ester was dissolved in 15 ml of THF and 0.43 g (2.7 mmol) of potassium permanganate, dissolved in 8 ml of water, was added to THF solution at 10° C. during 10 min. The reaction mixture stirred over night at RT. Reaction progress was monitored by TLC. Reaction mixture was filtered through celite and washed with THF and thus obtained mother liquor was concentrated under vacuo. Product was crystallized with ethyl acetate to afford 0.25 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.36 (9H, s), 1.78 (4H, m), 3.18 (1H, m), 3.66 (1H, m), 6.75 (1H, d), 6.94 (3H, m), 7.18 (2H, d), 7.36 (2H, s), 7.86 (4H, d), 8.38 (1H, d).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: CC(C)(C)c1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 4-tert. butyl-thiophenol.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C

Procedure:
A mixture containing 2-(chloromethyl)quinoline hydrochloride (100.0 g), 4-acetamidophenol (70.69 g) and milled anhydrous potassium carbonate (194 g) was stirred in DMF (1.2 L) using a mechanical stirrer for 48 hours. The mixture was carefully poured onto ice/water (3 L) with vigourous stirring. After the ice had melted, the solid was filtered and rinsed thoroughly with water. It was recrystallized from 95% ethanol and filtered to give the title compound in three crops.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:22]2[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: N#Cc1ccc(B(O)O)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(C#N)cc3)c(-c3ccc(C#N)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 29.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-cyanophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (15 mg, 0.038 mmol) as a yellow solid. MS: [M+H]+=394.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br.Br[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Br.[OH-].[K+]>O>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: BrCCNCCBr
Reactant: Cc1cccc(N)c1Cl
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(N2CCNCC2)c1Cl
Reaction time: 9 h
Yield: 56.1 %

Procedure:
To a mixture of 6.08 g of 2-chloro-3-methylaniline, 9 g of di(2-bromoethyl)amine hydrobromide and 4 ml of water was added a solution of 0.8 g of potassium hydorxide and 2.5 ml of water 3 times of 1 hour interval at 100° C., then the reaction mixture was stirred at the same temperature for 9 hours. To the resultant reaction mixture was added potassium hydroxide to make the mixture alkaline, and the mixture was extracted with diethyl ether, washed with water, dried with anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: 5%-methanol/chloroform), and obtained 3.41 g of 4-(2-chloro-3-methylphenyl)piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[N:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: NCC1CCNCC1
Solvent: CCO
Product: Oc1ccc(Br)cc1C=NCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.2 %

Procedure:
A mixture of 5-bromo-2-hydroxybenzaldehyde (170 g) and 4-(aminomethyl)piperidine (96.9 g) in ethanol (2.5 L) was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo to give 4-bromo-2-[N-(4-piperidylmethyl)iminomethyl]phenol (267 g) as a yellow solid m.p 35-38° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23]([NH:36][CH2:35][CH2:34][CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[O:24])[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26]
Reactant: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)NCCCN4CCOCC4)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.9 %

Procedure:
({3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]phenyl}-oxy)acetic acid (Compound 222, 17 mg, 48 umol) and 3-morpholinopropan-1-amine (5.8 mg, 40 umol) were dissolved in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL). To this solution was added 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The reaction mixture was stirred at room temperature for 15 hours and was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC to give 4 mg of product. 1H NMR (400 MHz, d6-DMSO): δ 8.31 (s, 1H), 8.17 (t, 1H), 7.96 (s, 1H), 7.87 (dd, 1H), 7.75 (d, 1H), 7.68 (s, 1H), 7.47 (t, 1H), 7.38 (s, 1H), 7.17 (dd, 1H), 6.92 (d, 1H), 4.61 (s, 2H), 3.61 (t, 4H), 3.21-3.16 (m, 2H), 2.30-2.22 (m, 6H), 2.20 (s, 3H), 1.63-1.57 (m, 2H). MS (EI): 480 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][O:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][O:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCCO1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
A suspension of 6-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (843 mg, 3 mmol), 5-chloromethyl-2-(trifluoromethyl)pyridine (704 mg, 3.6 mmol) and solid K2CO3 (830 mg, 6 mmol) in anhydrous DMF (10 mL) was stirred at 70° C. for 20 min. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction was diluted with water and extracted with EtOAc (40 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by trituration with CH2Cl2-hexanes to afford 1.10 g (84%) of the title compound as a yellow solid. LC/MS (method A): retention time=3.50 min, (M+H)+=440.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20]2[CH:25]=[N:24][N:23]([CH:26]([CH3:28])[CH3:27])[C:21]=2[N:22]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:26]([N:23]1[C:21]2[N:22]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20]=2[CH:25]=[N:24]1)([CH3:28])[CH3:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
Trifluoromethanesulfonic anhydride (5.23 g, 18.5 mmol) was added to a cooled solution of ethyl 6-hydroxy-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (4.2 g, 16.9 mmol) and pyridine (1.46 g, 18.5 mmol) in DCM (60 mL); and it was allowed to stirred at room temperature for 2 h. After completion of the reaction, saturated NaHCO3 solution (60 mL) was added to it and extraction was carried out using DCM (30 mL×3). The combined organic layers were washed with water (100 mL); brine (100 mL); dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was finally purified by silica gel column chromatography to provide pure the desired intermediate (5 g, 77.8% yield).
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.CC1C=CC(S(O[CH2:43][C@@H:44]2[CH2:48][O:47][C:46]([CH3:50])([CH3:49])[O:45]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:43][C@@H:44]6[CH2:48][O:47][C:46]([CH3:50])([CH3:49])[O:45]6)[CH:25]=5)[N:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(OC[C@@H]2COC(C)(C)O2)c1
Temperature: 90 °C

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(3-hydroxyphenyl)-5-methylpyridin-2-yl)cyclopropanecarboxamide (42 mg, 0.10 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (34 mg, 0.12 mmol) in DMF (1 mL) was added Cs2CO3 (65 mg, 0.20 mmol). The mixture was heated at 90° C. for 4 hours. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness to yield (R)-1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)-N-(6-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-phenyl)-5-methylpyridin-2-yl)cyclopropanecarboxamide which was used in next step without further purification.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10022.7 %

Procedure:
To a solution of benzenesulfonyl chloride (722 μL, 0.00566 mol), potassium carbonate (0.939 g, 0.00679 mol) in acetonitrile (15 mL, 0.29 mol) was added tert-butylamine (0.652 mL, 0.00623 mol). The resulting mixture was stirred at r.t. for 30 minutes, followed by filtration and concentration. The resulting residue was diluted with ethyl acetate, and the resulting solution was washed with water then with brine, then dried with MgSO4 followed by concentration. The crude material was purified by flash chromatography on silica gel with 40% AcOEt in hexanes to give the desired compound (121 g, 85% yield). MS (ESI): 236.0 (M+Na+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2Cc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCN2Cc1ccccc1
Yield: 79 %

Procedure:
A solution of compound 55e (80.2 mg, 0.3 mmol), and LiOH.H2O (50.4 mg, 1.2 mmol) in THF/H2O (1.2/1.2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55f (60 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 254.1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:27])[N:25]=1
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: Nc1nc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](CNC(=O)c1csc(N)n1)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1

Procedure:
The title compound was synthesized from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (380 mg, 1.45 mmol), 2-aminothiazole-4-carboxylic acid (217 mg, 1.5 mmol), HOBt (235 mg, 1.74 mmol), DIPEA (0.303 mL, 1.74 mmol) and EDCI (333 mg, 1.74 mmol) using DCM as solvent using the method of Example 34(d). Yield 92 mg. 1H NMR (400 MHz; CDCl3): δ 1.60 (d, 3H), 3.81 (m, 2H), 4.61 (m, 1H), 4.91 (s, 2H), 6.60 (d, 1H), 7.37 (s, 1H), 7.50 (d, 1H), 7.58 (m, 2H), 7.80 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:33][C@H:11]([CH2:12][O:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:10]([I:34])[CH2:9]1)[CH3:2]>C(O)(=O)C.O>[CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:33][C@H:11]([CH2:12][OH:13])[C@@H:10]([I:34])[CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](I)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Solvent: CC(=O)O
Solvent: O
Product: CCc1cn([C@H]2C[C@H](I)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 41.5 %

Procedure:
A solution of 720 mg of 2',3'-dideoxy-5-ethyl-3'-iodo-5'-O-trityluridine in a mixture of 16 ml of acetic acid and 4 ml of water was stirred and heated under reflux for 1 hour. The solvent was removed by evaporation and the residue was crystallized from a mixture of ethyl acetate and hexane to give 180 mg of 2',3'-dideoxy-5-ethyl-3'-iodouridine in the form of a white solid of melting point 161.5°-163° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.C([O:17][B:18]([CH:24]=[CH2:25])OCCCC)CCC.Cl>C1COCC1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH:25]=[CH:24][BH:18][OH:17]
Reactant: Brc1cccnc1
Reactant: C=CB(OCCCC)OCCCC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OBC=Cc1ccccn1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 3-bromopyridine (1.60 g, 10.0 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2.0 M in THF) (5.0 mL, 10 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred for 1 h. To the mixture was added vinylboronic acid dibutyl ester (3.4 mL) drop wise, and the mixture was stirred at room temperature for 18 h. Water was added and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.04 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH3:8])=[O:6].[N:25]([Sn](CCCC)(CCCC)CCCC)=[N+:26]=[N-:27].C([Al](CC)CC)C.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:5]([N:7]([CH3:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]1[NH:27][N:26]=[N:25][N:20]=1)=[O:6]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCC#N
Agent: CC[Al](CC)CC
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCc1nnn[nH]1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
A mixture of 3-bromo-4-chloro-N-[2-(3-cyano-propoxy)-phenyl]-N-methyl-benzamide (2.0 g, 4.9 mmol), azidotributyltin (4.03 mL, 14.7 mmol) and triethylaluminum (7.74 mL, 14.7 mmol, 25% in toluene) in toluene (25 mL) was heated at 80° C. for 5 hrs. The mixture was allowed to cool to room temperature and was acidified with 1N HCl. The mixture was extracted with DCM. The organic layer was washed with water and brine, and was dried. The filtrate was concentrated in vacuo and the residue purified by silica gel column chromatography (eluent: 3% MeOH in DCM) to afford 3-bromo-4-chloro-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide (1.93 g). MS [M+H]+: 451.9; tR=2.26 min. (method 1)
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].[Na+].O>[Cl:12][CH2:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ncccc1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1cccnc1CCl
Temperature: 0 °C
Yield: 80.5 %

Procedure:
Dissolve (3-fluoro-pyridin-2-yl)-methanol (215 mg, 1.69 mmol) in dichloromethane (10 mL) and cool to 0° C. Add thionyl chloride (160 μL, 2.20 mmol) and stir the reaction for one hour. Add dichloromethane (50 mL) and stir the reaction with saturated aqueous sodium bicarbonate (2×40 mL) and brine (2×40 mL). Separate and dry the organic portion over magnesium sulfate, filter, and concentrate under reduced pressure to provide 198 mg (80%) of product, which is used without further purification. MS: m/z 146, 148 [C6H5ClFN+1]+; 1H NMR (300 MHz, CDCl3): δ 8.41-8.44 (m, 1H), 7.41-7.47 (m, 1H), 7.28-7.34 (m, 1H), 4.75 (d, J=2.0 Hz, 2H); 19F NMR (282 MHz, CDCl3): δ-123.8.