Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:15])/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)C.[NH3:16]>CO>[ClH:1].[F:14][C:11]1[CH:10]=[CH:9][C:8](/[CH:7]=[CH:6]/[C:5]([NH2:15])=[NH:16])=[CH:13][CH:12]=1
Reactant: N
Reactant: CCOC(=N)/C=C/c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: N=C(N)/C=C/c1ccc(F)cc1
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A solution of E-3-(4-fluorophenyl)acrylimidic acid ethyl ester hyrochloride (0.86 g, 0.00374 moles) in dry methanol (20 ml) was treated with a solution of ammonia (0.064 g, 3.8 mmol) in dry methanol (0.51 ml) and the resulting solution was allowed to stand at room temperature for 48 h. The reaction mixture was evaporated to dryness, mixed with diethyl ether and evaporated to give E-3-(4-fluorophenyl)acrylamidine hydrochloride as a solid (0.75 g, 100%); 1H-NMR (d6-DMSO) 6.72, 6.79 (1H, d) 7.35 (2H, m), 7.67 (2H, m), 7.87, 7.94 (1H, d), 8.8, 9.15 (2×bs). MS (APCI+) M+1=165, C9H9FN2 requires 164.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4cccnc4F)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12i and 4-bromoanisole
Reaction SMILES: [I:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[CH2:10][O:11]C(=O)C)=[C:6]([I:16])[C:5]([C:17]([NH:19][CH2:20][CH:21]([O:27]C(=O)C)[CH2:22][O:23]C(=O)C)=[O:18])=[C:4]([I:31])[C:3]=1[NH:32][C:33]([NH:35][C:36]1[C:41]([I:42])=[C:40]([C:43]([NH:45][CH2:46][CH:47]([O:53]C(=O)C)[CH2:48][O:49]C(=O)C)=[O:44])[C:39]([I:57])=[C:38]([NH:58][C:59](=[O:65])[CH2:60][O:61]C(=O)C)[C:37]=1[I:66])=[O:34]>CO.[OH-].[Na+]>[I:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[CH2:10][OH:11])=[C:6]([I:16])[C:5]([C:17]([NH:19][CH2:20][CH:21]([OH:27])[CH2:22][OH:23])=[O:18])=[C:4]([I:31])[C:3]=1[NH:32][C:33]([NH:35][C:36]1[C:41]([I:42])=[C:40]([C:43]([NH:45][CH2:46][CH:47]([OH:53])[CH2:48][OH:49])=[O:44])[C:39]([I:57])=[C:38]([NH:58][C:59](=[O:65])[CH2:60][OH:61])[C:37]=1[I:66])=[O:34]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(NC(=O)Nc2c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CO)Nc1c(I)c(NC(=O)Nc2c(I)c(NC(=O)CO)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N,N'-bis[2,4,6-triiodo-3-(2-acetoxyacetamido)-5-(2,3-diacetoxypropylaminocarbonyl)phenyl]urea (0.88 g, 0.55 mmol) was dissolved in a mixture of methanol (10 ml) and 2M aqueous NaOH (2.5 ml). After stirring for 15 min at ambient temperature, pH was adjusted to 4 with a strongly acidic ion exchange resin, and, after filtration, evaporated to dryness. The residue was purified by preparative HPLC. Yield: 0.58 g (78%).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13].O>N1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:4][O:2][CH3:3])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CONS(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 63.6 %

Procedure:
Methoxylamine hydrochloride (0.95 g (11.4 mmol)) was suspended in pyridine (4.0 ml). To this, under cooling with ice and with stirring, 2-chlorobenzenesulfonyl chloride (2.11 g (10.0 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for one hour. Water (50.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.41 g (64%) of 2-chloro-N-methoxybenzenesulfonamide as pale yellow crystals.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10](N)[CH:11]=[N:12][CH:13]=1.N([O-])=[O:16].[Na+].[OH-].[Na+].[Na+].[Cl-]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([OH:16])[CH:11]=[N:12][CH:13]=1
Reactant: COc1cncc(N)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1cncc(O)c1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 30.2 %

Procedure:
A mixture of concentrated sulfuric acid (18 M, 2.83 mL), water (3.84 mL) and crushed ice (6.60 g) was added to 5-methoxy-3-pyridylamine (1.64 g, 13.23 mmol). The cold mixture (0-5° C.) was stirred for 10 min and a solution of sodium nitrite (0.91 g, 13.23 mmol) in water (2.7 mL) was then added. After stirring for 10 min, a boiling solution of concentrated sulfuric acid (8.6 mL) and water (6.6 mL) was added. The mixture was heated until all solids dissolved. Ice (5.0 g) was added to cool the solution. The pH was adjusted to 8 with 10% NaOH solution. Saturated NaCl solution (100 mL) was added, and the mixture was extracted with ethyl acetate (4×100 mL). The combined ethyl acetate extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give 0.50 g (30.1%) of a brown oil.
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])(=O)=O)=CC=1.C[O-].[Na+]>CO>[N:12]1[CH2:14][C:13]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=NOS(=O)(=O)c1ccc(C)cc1)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1cncc(C2=NC2)c1
Reaction time: 2 h

Procedure:
100 g of 1-(3-pyridinyl)-ethanone O-[(4-methylphenyl)sulphonyl]-oxime is introduced at 20° C. under a nitrogen atmosphere into a solution containing 400 ml of anhydrous methanol and 23.45 g of sodium methylate. Agitation is carried out for 2 hours at 20˜22° C. and a suspension containing the sought product is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])([O-])=O.Cl[Sn]Cl.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=Cc1ccccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=Cc1ccccc1N
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of methyl 2-nitrocinnamate (8) (11.03 g, 53.24 mmol) in ethyl acetate (200 ml) was added SnCl2.H2O (60.06 g, 266.19 mmol) at room temperature, and the resulting solution was stirred at 70° C. for 60 minutes. After the reaction was completed, the solution was allowed to cool to room temperature, basified with a saturated aqueous solution of sodium bicarbonate to weak basicity, and filtered with celite. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane=1:5) to give the target compound (8.50 g, 90%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][Cl:14]>O.C(O)C>[O:7]([CH2:11][CH2:12][CH2:13][Cl:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ClCCCOc1ccccc1

Procedure:
A mixture of phenol (1 mole), sodium hydroxide (1 mole) and 3-bromo-1-chloro-propane (2 moles) in water (1000 ml) and ethyl alcohol (250 ml) is refluxed during 20 hours, with stirring. After cooling, sodium hydroxide (30 g) is added to the reaction medium which is then extracted with methylene chloride. The organic phase is washed with water to neutral pH. It is then dried over sodium sulfate, concentrated in vacuo over a water-bath and the residual oil is distilled. B.p. = 118°-120° C./15 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH:8]2[CH2:10][CH:9]2[CH2:11][NH:12]C(=O)OCC2C=CC=CC=2)=[N:6][CH:7]=1>[Pd].CO>[F:1][C:2]1[CH:7]=[N:6][C:5]([CH:8]2[CH2:10][CH:9]2[CH2:11][NH2:12])=[N:4][CH:3]=1
Reactant: O=C(NCC1CC1c1ncc(F)cn1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC1CC1c1ncc(F)cn1
Reaction time: 2 h
Yield: 48.1 %

Procedure:
A mixture of benzyl ((2-(5-fluoropyrimidin-2-yl)cyclopropyl)methyl)carbamate (180 mg, 0.597 mmol), 10% palladium on carbon (63 mg) in MeOH (10 mL) was shaken in a Parr shaker under hydrogen (10 psi) for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue purified by silica gel chromatography using 0-20% 2.0 M ammonia in MeOH/EtOAc as the eluent to give (2-(5-fluoropyrimidin-2-yl)cyclopropyl)methanamine as a yellowish oil (48 mg, 48%). 1H NMR (400 MHz, CHLOROFORM-d) d 8.40 (s, 2H), 2.81-2.66 (m, 2H), 2.11 (dt, J=8.5, 4.4 Hz, 1H), 1.70-1.58 (m, 1H), 1.30 (bs, 2H, NH2), 1.28 (m, 1H), 0.97 (ddd, J=8.5, 6.0, 4.3 Hz, 1H). LCMS: M+1=168.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28][C:29]([F:39])([F:38])C1C=CC=CC=1C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:29]([F:39])([F:38])[F:28])[O:6][C:7]=1[CH3:8]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccccc2C(F)(F)F)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 2-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-methyl-2-(2-trifluoromethylphenyl)oxazole.
Reaction SMILES: C(C(O)=O)(F)(F)F.[O:8]=[C:9]1[N:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=2[N:10]1[CH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>C(Cl)Cl>[O:8]=[C:9]1[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=2[N:10]1[CH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(C2CCSCC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(=O)n(C2CCSCC2)c2ccccc21
Reaction time: 3 h

Procedure:
CF3CO2H (1 mL) was added to a solution of tert-butyl (2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step C (169 mg, 0.485 mmol) in CH2Cl2 (3 mL). After 3 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=293 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[C:23](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][C:15]([O:17][CH3:23])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC1(c2cccc(O)c2)CCCCC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1(c2cccc(O)c2)CCCCC1
Temperature: 25 °C
Yield: 52 %

Procedure:
The crude 2-(1-(3-hydroxyphenyl)cyclohexyl)acetic acid 105.C (1.01 g) was dissolved in MeOH (15 mL) and a catalytic (˜10 drops) amount of concentrated sulfuric acid was added. The mixture was then refluxed for 16 hours and then cooled to room temperature. The reaction was then made basic with saturated sodium bicarbonate solution and concentrated to dryness. The residue was then dissolved in EtOAc and water and the layers were separated. The aqueous layer was extracted (2×75 mL) with EtOAc. The combined organic layers were then washed with brine (1×75 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 0 to 15% EtOAc: DCM) to give methyl 2-(1-(3-hydroxyphenyl)cyclohexyl)acetate 105 (560 mg, 52% yield). MS ESI (pos.) m/e: 266.2 (M+H2O)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:11]C)[C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])C.Cl[C:14]#[N:15]>O.C1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][N:3]([CH3:11])[C:4](=[O:10])[CH:5]([C:14]#[N:15])[C:6]([CH2:8][Cl:9])=[O:7]
Reactant: CCN(CC)C(=O)CC(=O)CCl
Reactant: N#CCl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: CN(C)C(=O)C(C#N)C(=O)CCl
Yield: 75.3 %

Procedure:
10.0 gm. (0.05 mole) of copper acetate was dissolved hot in 150 ml of H2O and added to a solution of 19.1 gm. (0.1 mole) of γ-chloroacetoacetic acid diethyl amide in 150 ml of benzene. After brief stirring the green benzene solution was separated and dried over MgSO4. Then 6.2 gm. (0.1 mole) of ClCN were introduced into the benzene solution -- the temperature was kept at 20° to 30° C. The precipitated CuCl2 was filtered off and the benzene solution was precipitated. 14.2 gm of α-cyano-γ-chloroacetoacetic acid dimethylamide was obtained, which corresponds to 65.6 percent of theoretical.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)[CH3:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: CCc1ccccc1B(O)O
Reactant: Cn1c(=O)[nH]c2cccc(Br)c21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1cccc2[nH]c(=O)n(C)c12
Temperature: 100 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
A mixture of 280 mg (1.23 mmol) of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 222 mg (1.48 mmol) of 2-ethylphenylboronic acid, 113 mg (0.0123 mmol) of tris(dibenzylideneacetone)dipalladium, 29 mg (0.0615 mmol) of X-Phos and 522 mg (2.46 mmol) of potassium phosphate in 9 mL of toluene was stirred at 100° C. for 4 hours. After cooling, the reaction mixture was diluted with water and ethyl acetate and passed through celite. The filtrate was extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 25-65% ethylacetate/n-hexane gradient mixture to give 200 mg (64%) of the title compound.
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:18])=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:5][C:4]1=[O:19]>O1CCCC1.[Ni].O>[CH3:18][C:8]1[CH:7]=[C:6]2[C:11]([CH2:3][C:4](=[O:19])[NH:5]2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: CSC1C(=O)Nc2cc(C)cc(-c3ccccc3)c21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(c(-c3ccccc3)c1)CC(=O)N2

Procedure:
To a slurry of 11.8 grams (0.044 mole) of 3-methylthio-6-methyl-4-phenylindoline-2-one in 500 milliliters of tetrahydrofuran are added 100 grams of a commercial Raney nickel/water preparation portionwise over a two-hour period. The mixture is filtered through Celite and the filtrate concentrated. A small amount of methylene chloride is added to the residue and the resulting solid is collected by filtration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:20](=[O:34])[CH:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[O:34]=[C:20]1[CH:19]=[C:18]([CH2:17][NH:16][C:13](=[O:15])[C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[CH:12][N:11]=2)[CH:23]=[CH:22][N:21]1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=1
Reactant: O=C(O)c1ccc(-c2cnccn2)cn1
Reactant: NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1)c1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(pyrazin-2-yl)picolinic acid 41-4 (28 mg, 0.14 mmol), 4-(aminomethyl)-1-(2-(trifluoromethyl)pyridin-4-yl)pyridin-2(1H)-one 56-7 (35 mg, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (49 mg, 0.13 mmol) in DMF (1.0 mL) was added DIEA (0.09 mL, 0.52 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-((2-oxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2-dihydropyridin-4-yl)methyl)-5-(pyrazin-2-yl)picolinamide 56 as a white solid. MS m/z 453.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.57 (t, 1H), 9.40 (d, 1H), 9.36 (dd, 1H), 8.86 (d, 1H), 8.77 (dd, 1H), 8.69 (m, 2H), 8.16 (dd, 1H), 8.07 (d, 1H), 7.84 (dd, 1H), 7.73 (d, 1H), 6.37 (dd, 1H), 6.31 (b, 1H), 4.36 (d, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]([C:20](O)=[O:21])[CH2:13][CH2:12]2.O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]([CH2:20][OH:21])[CH2:13][CH2:12]2
Reactant: COc1cc2c(cc1OC)C(C(=O)O)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(CO)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
To 3.1 g of lithium aluminium hydride suspended in 30 ml of tetrahydrofuran there are added 18 g of (5,6-dimethoxyindan-1-yl)carboxylic acid [described in J. Pharm. Sci. (1968) 57 (6) 1013] dissolved in 180 ml of tetrahydrofuran. After stirring at room temperature for 18 hours, there are added dropwise, with cooling, 2.2 ml of water, then 1.7 ml of 20% sodium hydroxide, and finally 7.6 ml of water. The mineral salts are then filtered and rinsed, and the filtrate is evaporated to dryness. In this manner, 16.5 g of (5,6-dimethoxyindan-1-yl)methanol are obtained in the form of an oil, in a yield of 98%.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1)[CH2:4][OH:5].[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[OH:5][CH2:4][C@H:3]([NH:2][C:18](=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: N[C@@H](CO)c1cccc(N2CCOCC2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)N[C@@H](CO)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
Mixture of (R)-2-Amino-2-(3-morpholin-4-yl-phenyl)-ethanol hydrochloride (70 mg, 0.24 mmol), cinnamic acid (35 mg, 0.24 mmol), EDC (91 mg, 0.47 mmol), DMAP (29 mg, 0.24 mmol), triethyl amine (0.13 mL, 0.95 mmol) in dichloromethane (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and purified by flash chromatography with 60% acetone/hexanes to provide the title compound as a white solid (57 mg, 68% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21]C)[N:12]2[CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.[OH-].[Na+]>CO.O1CCOCC1>[NH2:23][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:21])[N:12]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Reaction time: 4 h
Yield: 66.8 %

Procedure:
2-Butoxy-8-methoxy-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-6-amine (97 mg) was dissolved in methanol (2 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (1 mL). The reaction mixture was stirred for 4 hours. The reaction was stripped to dryness. Water (2 mL) and methanol (15 mL) was added to the residue and then neutralised by the addition of 2N sodium hydroxide solution. The above was stripped to near dryness (small quantity of water remaining) and the solid thus obtained was filtered (transferred and washed the solid with water (2 mL, 3 times)). The solid was dried under suction before being dried further in vacuo (50° C.) for 2 hours. This afforded the title compound as a white solid (62 mg).
Reaction SMILES: BrC1C=CC(S[CH2:9][C:10]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=CC=1.Cl[C:22]1[CH:27]=CC=C(C(OO)=O)[CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:14][C:11]1([C:10]2([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[CH2:9][O:15]2)[CH2:12][CH2:27][CH2:22][CH2:23][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)C(O)(CSc1ccc(Br)cc1)c1cncs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C2(c3cncs3)CO2)CCCCC1

Procedure:
To 1.00 g (2.7 mmol) of 1-[(4-bromophenyl)sulphanyl]-3,3-dimethyl-2-(1,3-thiazol-5-yl)butan-2-ol dissolved in 100 ml of dichloromethane was added, at room temperature, 0.70 g (4.0 mmol) of meta-chloroperbenzoic acid, and the reaction mixture was stirred at room temperature for 16 h. After addition of saturated aqueous sodium hydrogen carbonate solution, the organic phase was removed and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried in the sodium sulphate, filtered and concentrated. The crude product was subsequently purified by column chromatography (1:1 tert-butyl methyl ether/petroleum ether). This gave 0.80 g (76%) of compound 8 and 0.25 g (23%) of compound 9.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[O:4][CH:5]=[C:6]([CH2:8][CH2:9][C:10](OC)=[O:11])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:15][Si:2]([CH3:1])([CH3:14])[C:3]1[O:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=1
Reactant: COC(=O)CCc1coc([Si](C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(CCCO)co1
Reaction time: 3 h

Procedure:
A solution of methyl 3-(2-trimethylsilyl-4-furyl)propionate (from above) in tetrahydrofuran (3 ml) was added dropwise to a suspension of lithium aluminum hydride (27 mg) in tetrahydrofuran (4 ml) at room temperature. After 3 hours, the mixture was quenched with ethyl acetate and extracted with ether. Evaporation of the dried (magnesium sulphate) extracts gave the title alcohol, which was used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][NH:5][CH2:6][C:7]([CH3:10])([NH2:9])[CH3:8].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.CO>C(Cl)Cl>[CH3:11][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:6][C:7]([CH3:8])([CH3:10])[NH:9][C:17]1=[O:18]
Reactant: CN(C)CCNCC(C)(C)N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN1CC(C)(C)NC1=O
Reaction time: 20 h
Yield: 1.8 %

Procedure:
To a solution of N1-(2-(dimethylamino)ethyl)-2-methylpropane-1,2-diamine (23.2 mmol) in CH2Cl2 (50 ml) was added CDI (4.51 g, 27.8 mmol). The solution was stirred for 20 h, concentrated in vacuo, the resulting residue suspended in 800 ml diethyl ether, washed with 3× 200 ml 1M Na2CO3, 200 ml sat. NaCl, dried on MgSO4, and concentrated in vacuo. Flash chromatography (2.5%→20% MeOH:CH2Cl2) afforded the title compound as a clear oil (79.3 mg, 0.428 mmol, 2%) as well as additional material heavily contaminated with imidazole g). 1H NMR (CDCl3, 400 MHz) δ 1.24 (s, 6H), 2.23 (s, 6H), 2.41 (m, 2H), 3.24 (s, 2H), 3.34 (m, 2H), 4.96 (s, 1H). ESI/APCI (pos) expected for C9H19N3O: 185.15. Found: 186 (MH+).