Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[CH3:3][N:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:20][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([N:4]([CH3:3])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Methyl iodide (227 mg, 0.1 mL, 1.68 mmol) was added drop wise to a suspension of 4-(Methyl-phenyl-amino)-benzoic acid (120 mg, 0.56 mmol) and K2CO3 in DMF (5 mL). The resulting mixture was heated at 80° C. with stirring overnight. The mixture was filtered, cold water was then added, and the product was extracted with EtOAc. The organic layer was washed with saturated brine solution and dried over Na2SO4. The organic layer was then concentrated under reduced pressure to get the residue The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 5% EtOAc in Hexane as eluent) to afford 85 mg (75% yield) of 4-(Methyl-phenyl-amino)-benzoic acid methyl ester. 1H-NMR (CDCl3): δ 7.8 (d, 2H), 7.4 (T, 2H), 7.2 (m, 2H), 6.8 (d, 2H), 3.8 (s, 3H), 3.2 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH:15]2[CH2:17][CH2:16]2)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.Cl[Pd]Cl>[Cl:18][C:19]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:8]([CH:15]3[CH2:17][CH2:16]3)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Yield: 84.9 %

Procedure:
A mixture of N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (5 g, 15.66 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (as prepared in Example 1, step 1; 4.13 g, 15.66 mmol), sodium carbonate (15.66 mL, 31.3 mmol) and PdCl2 (dppf).CH2Cl2 adduct (0.320 g, 0.392 mmol) in DMF (100 mL) was heated to 100° C. for 25 min. After concentration, the residue was dissolved into CH2Cl2 and filtered through a pad of Na2SO4. The solution was absorbed into celite and concentrated. The residue was purified by flash column (ethyl acetate/heptane, 30%-50%-80%, v/v) and yielded the title compound as a colorless solid (5.0 g). Chiral separation by chiral HPLC (Chiralpak AD-H using Supercritical fluid chromatography. 25% Methanol at 65 grams per minute with supercritical CO2) afforded enantiomer 1 (S)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=3 min), and enantiomer 2 (R)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=4 min). ESI-MS m/z: 376.2 [M+H]+, 1H NMR (400 MHz, CDCl3): δ 0.37-0.40 (m, 1H), 0.51-0.55 (m, 1H), 0.57-0.68 (m, 1H), 0.70-0.77 (m, 1H), 1.15-1.27 (m, 3H), 2.70-2.88 (m, 2H), 3.85 (dd, J=5 Hz, 9 Hz, 1H), 4.68 (d, J=5 Hz, 1H), 7.53 (dd, J=1.5 Hz, 8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.80 (t, J=2 Hz, 1H), 8.67 (d, J=2 Hz, 1H), 8.72 (d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[CH:5][C:4]=1[CH:21]=[CH2:22].[H][H]>O1CCCC1.[Pd]>[CH2:21]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:3]=1[O:2][CH3:1])[CH2:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])[CH3:22]
Reactant: [H][H]
Reactant: C=Cc1cc(CN2C(=O)c3ccccc3C2=O)ccc1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cc(CN2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 92.1 %

Procedure:
2.75 g of N-(4-methoxy-3-vinylbenzyl)phthalimide was dissolved in 50 ml tetrahydrofuran, 0.1 g of 10% Pd-C was added thereto, and the mixture was stirred for 40 min in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography to give 2.55 g of N-(3-ethyl-4-methoxybenzyl)phthalimide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20].C(O)C>O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][CH2:19][CH2:18][O:17][CH3:16])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=1
Reactant: Cc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: COCCN
Solvent: O
Solvent: CCO
Product: COCCNc1cc(Cl)nc(-c2ccc(C)cc2)n1

Procedure:
A solution of 7.2 g. of 4,6-dichloro-2-(p-tolyl)pyrimidine and 4.5 g. of β-methoxyethylamine in 35 ml. of absolute ethanol is refluxed for 15 minutes. Pouring of the resulting solution into 700 ml. of water causes separation of a gummy material which solidifies on standing. The crude product weighs 7.3 g. and recrystallization from n-heptane affords 4-chloro-6-[2-(methoxy)ethylamino]-2-(4-tolyl)pyrimidine, 70°-72°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CI
Reactant: COc1cc(Br)ccc1NC(=O)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1N(C)C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide (1.0 g, 3 mmol) in dimethylformamide (20 mL) at 0° C. was treated with pre-washed (3 times with heptane) sodium hydride (0.158 g, 6.6 mmol). The reaction mixture was stirred for 1 h at 0° C. Methyl iodide (0.511 g, 3.6 mmol) was added drop-wise, and the solution stirred for 15 min at 0° C. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction did not go to completion over night; additional methyl iodide (0.511 g, 3.6 mmol) was added and the reaction mixture stirred over night. The reaction mixture was quenched with water (30 mL). Ethyl acetate was added, and the layers were partitioned. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting 3:1 heptane:ethyl acetate, and afforded 0.729 g (70%) of N1-(4-bromo-2-methoxyphenyl)-N1-methyl-3-phenylpropanamide. 1H NMR (DMSO-d6, 400 MHz) δ 7.330-7.326 (s, 1H), 7.235-7.178 (m, 2H), 7.161-7.116 (m, 3H), 7.058-7.040 (m, 2H), 3.811 (s, 3H), 3.002 (s, 3H), 2.753-2.708 (m, 2H), 2.282-2.204 (m, 1H), 2.138-2.061 (m, 1H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 7.366 min (96%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19]([CH2:25][C:26]#[N:27])(=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([C:19]1[CH:25]=[C:26]([NH2:27])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100 mL) and treated with triethylamine (20.2 g). The mixture was stirred at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight. The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g, 70%). 1H NMR (DMSO-d6): δ 7.5 (d, 2H), 7.0 (d, 1H), 6.4 (s, 1H), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:5]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1NCc2cc(Br)ccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(Br)cc2CN1CC(F)(F)F
Temperature: 0 °C

Procedure:
5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO3 (10 mL) was carefully added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C10H7BrF3NO [M+H]+: 294. Found: 294.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>C(#N)C>[CH3:15][O:14][C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1)=[O:13].[CH2:24]([N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH3:23]
Reactant: COC(=O)c1ccc(C(Br)C(=O)O)cc1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(C(Nc2ccccc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
2-Bromo-2-(4-(methoxycarbonyl)phenyl)acetic acid (700 mg, 2.56 mmol), aniline (0.23 mL, 2.56 mmol), and DIPEA (0.94 mL, 5.38 mmol) are dissolved in acetonitrile (5 mL). The reaction is stirred at 100° C. under microwave irradiation for 15 minutes. Acetonitrile is evaporated and the residue is dissolved in DCM and washed with water and brine. The organic layer is dried (Na2SO4), filtered and evaporated. The crude compound is purified by flash chromatography (DCM/MeOH=9/1) to obtain intermediate I142 as a white solid (381 mg, 37% yield).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].Cl.[NH2:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[C:18]([F:29])[CH:17]=2)[CH2:11]1.N1C=CC=CC=1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[F:29][C:18]1[CH:17]=[C:16]([N:12]2[CH2:11][CH:10]([CH2:9][NH:8][C:3](=[O:4])[CH:2]([F:6])[F:1])[O:14][C:13]2=[O:15])[CH:21]=[CH:20][C:19]=1[N:22]1[CH:23]=[CH:24][C:25](=[O:28])[CH2:26][CH2:27]1
Reactant: NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)C(F)F
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C1C=CN(c2ccc(N3CC(CNC(=O)C(F)F)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Difluoroacetic acid (0.031 mL, 0.48 mmol) is added to a solution of 1-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-2,3-dihydro-1H-pyridin-4-one hydrochloride (0.150 g, 0.44 mmol) in DMF (1.5 mL) with pyridine (0.071 mL, 0.88 mmol), followed by addition of diisopropylcarbodiimide (0.076 mL, 0.48 mmol). The mixture is stirred at r.t. for 1 h. Most of the solvent is removed under high vacuum, and the product is purified by silica gel column chromatography (eluent: 2% MeOH in DCM). The chromatography is repeated (eluent: 1% MeOH in DCM) to afford N-{3-[3-Fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl} difluoroacetamide as a white solid. Yield 0.065 g (39%). MS (m/z): 384 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.36 (t, J=5.5 Hz, 1H), 7.82–7.49 (m, 4H), 6.44 (t, J=53.6 Hz, 1H), 5.18 (d, J=7.7 Hz, 1H), 5.03–4.98 (m, 1H), 4.38–4.32 (m, 1H), 4.07 (t, J=7.4 Hz, 2H), 3.97 (dd, J=6.3 and 9.3 Hz, 1H), 3.72 (t, J=5.5 Hz, 1H), 3.51–3.49 (m, 2H), 2.69–2.64 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C1COCC1.O>[S:17]([N:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(OCC4CO4)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A solution of glycidyl 4-indolyl ether (compound 1a) (1.0 g, 5.3 mmol) in THF (5 mL) was cooled to 0° C., and sodium hydride in mineral oil (60%, 0.42 g, 10.6 mmol) and tosyl chloride (1.2 g, 6.3 mmol) were added. After being stirred at this temperature for 1 h, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with CHCl3 (3.50 mL). The combined organic layers were dried with Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel with benzene/acetone mixtures to give the glycidyl N-tosyl-4-indolyl ether (compound 1b) (1.5 g, 82%) as a white solid. See FIG. 18.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)[C:13](O)=[O:14])=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)[C:13]([Cl:3])=[O:14])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Oc1ccc(F)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(Oc1ccc(F)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.45 g (0.096 mol) of freshly distilled thionyl chloride are added to a suspension of 28.65 g (0.077 mol) of 2-(4-chloro-phenyl)-2-(4-fluoro-3-trifluoromethylphenoxy)-acetic acid in 35 ml of dry chloroform. The mixture is stirred for 30 minutes at ambient temperature and is then heated at the reflux temperature until all the acid has dissolved (about 6 hours). The solution is evaporated to dryness under reduced pressure and 2-(4-chlorophenyl)-2-(4-fluoro-3-trifluoromethyl-phenoxy)-acetyl chloride is obtained in the form of an oil, which is used without further purification for the next stage of the synthesis.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]2[S:6][C:7]([C:9]3[C:10]([NH2:31])=[N:11][CH:12]=[C:13]([C:15]4[N:19]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[N:18]=[N:17][N:16]=4)[CH:14]=3)=[CH:8][C:4]=2[CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][C:36]=1[C:44]([F:47])([F:46])[F:45]>O1CCCC1.C(OCC)(=O)C>[NH2:31][C:10]1[C:9]([C:7]2[S:6][C:5]3[CH:32]=[CH:33][C:2]([NH:1][C:42]([NH:41][C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[C:36]([C:44]([F:46])([F:45])[F:47])[CH:37]=4)=[O:43])=[CH:3][C:4]=3[CH:8]=2)=[CH:14][C:13]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26])[N:18]=[N:17][N:16]=2)=[CH:12][N:11]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnnc1-c1cnc(N)c(-c2cc3cc(N)ccc3s2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnnc1-c1cnc(N)c(-c2cc3cc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)ccc3s2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirring solution of 3-(5-aminobenzo[b]thiophen-2-yl)-5-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-tetrazol-5-yl)pyridin-2-amine (123 mg, 0.256 mmol, 1 eq) in anhydrous tetrahydrofuran (3 mL) under nitrogen atmosphere was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (58 mg, 1 eq) and the reaction mixture was stirred at room temperature for three hours. The reaction was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure and loaded onto silica. The mixture was subject to a gradient column chromatography (EtOAc-Hex 1:5 to 2:1) to give 1-(2-(2-amino-5-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea as a white solid in the amount of 130 mg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].O>CN(C=O)C>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([O-:16])=[O:15]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Piperazine (12.9 g) was dissolved in DMF (100 mL), and a solution of 2-fluoronitrobenzene (7.06 g) in DMF (30 mL) was added dropwise. The mixture was stirred at room temperature for 3 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to give 1-(2-nitrophenyl)piperazine (7.7 g) as a red oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15]>O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[C:1]1[N:15]=[N:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=2)[CH:2]=1
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Reactant: C#Cc1n[nH]c2ccc(C)cc12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
3-Ethynyl-5-methyl-1H-indazole (1.0 g; 6.4 mmol; 1.0 eq.) and 4-azidobenzaldehyde (prepared as described in Chem. Med. Chem. (2009), 4(7), 1182-1188; 1.30 g; 7.04 mmol; 1.1 eq.) were dissolved in 1,4-dioxane (15 mL). D-(−)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) followed by a solution of copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) in water (1.5 mL) were added and the reaction mixture was stirred at 90° C. for 3.5 hours. To complete the reaction more D-(−)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) and copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) were added again and the reaction mixture was heated at 10° C. for 8 h. 1,4-dioxane was removed under reduced pressure an the residue was sonicated in a mixture of EtOAc and water (1:1). The resulting solid was filtered and dried to afford the title compound as a beige solid (1.94 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ: 13.29 (brs, 1H), 10.11 (s, 1H), 9.46 (s, 1H), 8.34 (d, J=8.6 Hz, 2H), 8.18 (d, J=8.6 Hz, 2H), 8.14 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.28 (dd, J=8.4 Hz, 1.4 Hz, 1H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:19](=[O:34])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C@@H:21]([CH3:22])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>N1C=CC=CC=1.C(OCC)(=O)C>[C:43]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[C@H:21]([CH3:22])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:34])=[CH:37][CH:38]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1C2N(C(=O)NCc3ccccc3)CCC(=O)N2[C@@H](Cc2ccc(O)cc2)C(=O)N1Cc1cccc2ccccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)[C@@H](C)C3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
To a solution of (6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in pyridine (1 ml), acetic anhydride 1 ml (10.579 mmol) was added and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with 10% citric acid (10 ml) 3 times and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound 39.3 mg (61%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CCOCC>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:11][CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:13])[CH3:12])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of 2-tert-butoxycarbonylamino-2-methyl-1-propanol (5.7 g, 30.11 mmol) and powdered NaOH (6.7 g, 0.151 mol) in Et2O (200 mL) was added p-toluenesulfonyl chloride (6.9 g, 36.14 mmol) at room temp. The stirred resulting mixture was heated under reflux for 8 hr. After cooling, ice-water (100 mL) was added to the solution. Separated Et2O layer was washed with brine, dried over Na2SO4, and evaporated. To the residue was added n-hexane and triturated. The solid was collected to afford 8.5 g (82.2%) 2-tert-butoxycarbonylamino-2-methyl-1-propyl p-toluenesulfonate as a crystalline material. 1H-NMR (CDCl3) δ1.26 (s, 6H), 1.38 (s, 9 H), 2.37 (s, 3H), 4.05 (s, 2H), 4.49 (br, 1H), 7.34 (d, J=7.8 Hz, 2H), 7.78 (d, J=7.8 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>Cl>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCSC2)cc1
Agent: Cl
Product: Nc1ccc(CN2CCSC2)cc1
Yield: 61.8 %

Procedure:
3-(4-nitrobenzyl)-thiazolidine (1.1 g, 5 mmoles) is put into solution in 10 ml concentrated hydrochloric acid at 0° C. Dihydrated tin chloride (7.7 g, 34 mmoles) is added in portions, the mixture is heated for 2 hours under reflux and the acid is evaporated off under reduced pressure. The residue is then taken up in 20 ml of water and neutralized with a 2N soda solution (approximately 100 ml). 100 ml of dichloromethane is added to the medium and the whole is filtered on celite in order to eliminate the salts in suspension. The organic phase is extracted, washed 3 times with 50 ml of water, dried, filtered and evaporated to dryness under reduced pressure. The expected product is purified on silica gel in a dichloromethane/methanol (98/2) mixture and is obtained in the form of of a beige powder (0.6 g, 63%). Melting point: 73-74° C.