Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:3](OCC)=[O:4].[BH4-].[Na+].[BH4-]>C(O)C>[NH2:1][C@H:2]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][OH:4]
Reactant: CCOC(=O)[C@H](N)CC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N[C@@H](CO)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
The process is performed as in Example 1, starting with 6.2 g of ethyl (2R)-2-amino-3-cyclohexylpropionate and 1.93 g of sodium borohydride in 120 cm2 of absolute ethanol at about 5° C. for 10 minutes. The medium is warmed to room temperature and stirred for a further 3 h 30 minutes. After cooling again to about 5° C. and addition of a further 40.94 g of borohydride, followed by stirring at a temperature in the region of 20° C. for 65 hours, the reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. A solid is obtained, which is purified by chromatography under a pressure of argon (100 kPa) on a column of silica gel (particle size 40-63μ; 320 g), eluting with pure methanol. The fractions containing the expected product are collected. These fractions are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 5.16 g of (2R)-2-amino-3-cyclohexyl-1-propanol are obtained in the form of a sticky white solid. (Rf=0.25 in methanol on a Merck 60F254R silica plate)
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO.Cl.O1CCOCC1>[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Tert-butyl 4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (0.587 g, 1.04 mmol) was dissolved in 1:1 CH2Cl2/methanol and 4N HCl in dioxane was added and stirred at ambient temperature for 1 hour. The reaction was concentrated and dried in vacuum oven. The HCl salt was partitioned between 5% MeOH in CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (0.473 g, 98.0% yield).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Mercapto-4-phenoxy-5-sulfamylbenzoic acid (0.6 g) is suspended in water (20 ml) and the pH is adjusted to 8 by addition of 1 N sodium hydroxide. Benzyl bromide (0.35 g) is added to the resulting solution, and the reaction mixture is stirred for 2 hours at room temperature. After cooling, the precipitated sodium salt of 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration. The salt is dissolved in hot water (60 ml) and the solution acidified by addition of 1 N hydrochloric acid. After cooling, the precipitated 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration and recrystallized from aqueous ethanol to yield the desired compound with a melting point of 234°-236°C., after drying in vacuo.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[CH:23][C:24]#[N:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][CH3:29].[H][H]>CO.C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][CH2:23][C:24]#[N:25])([CH2:20][CH2:21]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][CH3:29]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=CC#N)(CC3)CC4)nc2n(CCC)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC#N)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A solution of 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylonitrile (110 mg, 0.278 mmol) in MeOH (20 ml) and CH2Cl2 (5 ml) was hydrogenated using Pd on carbon (10 mol %) and a ballon of hydrogen affixed to a 3-way stopcock/ground glass adapter. After stirring overnight, the mixture was degassed, filtered through Celite and concentrated in vacuo to give a brittle foam (100 mg, 90%). 1H NMR (400 MHz, CDCl3); δ 0.93 (coincident triplets, 6H), 1.53 (m, 6H),1.57 (t, 2H), 1.67 (m, 2H), 1.77 (m, 2H), 2.00 (m, 6H), 2.24 (t, 2H), 3.99 (t, 2H), 4.05 (t, 2H), 12.17 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N+:16]([O-])=O)=[CH:4][CH2:3]1.[Cl-].[NH4+]>C(O)C.[Cl-].[Na+].O.[Fe]>[CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[NH2:16])=[CH:4][CH2:3]1
Reactant: COc1ccc(C2=CCC(C)(C)CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=CCC(C)(C)CC2)c(N)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
To a solution of 1-(4,4-dimethylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene (3.5 g, 13.4 mmol) prepared in Example (1c) in ethanol (30 mL) were added a solution (5 mL) of aqueous ammonium chloride (2.9 g, 54 mmol) and iron powder (1.5 g, 26.8 mmol), and the mixture was stirred at an external temperature of 90° C. for 1 hour and 30 minutes. The reaction mixture was passed through Celite, brine was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give 3.35 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:22]3[CH2:23][CH2:24][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:27]3)=[C:15]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)N1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCN(c2ccc(Nc3cc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
A mixture of 2,5-dichloro-4-iodopyridine (0.40 g, 1.46 mmol), 7-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (0.421 g, 1.46 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.051 g, 0.09 mmol), cesium carbonate (0.952 g, 2.92 mmol) and palladium(II) acetate (0.013 g, 0.06 mmol) was suspended in DMA (15 mL). The mixture was heated at 100° C. for 1 hour in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 7-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (0.630 g, 99% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.01-1.18 (3H, d), 2.60-2.64 (4H, m), 3.04-3.09 (5H, m), 4.51 (2H, s), 7.16 (1H, d), 7.29 (1H, s), 7.50 (1H, d), 8.28 (1H, s), 9.59 (1H, s); Mass spectrum: m/z (ESI+) (M+H)=434.0 and 436.0 and 438.0.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[CH:20]=O>C(O)C.Cl.C(O)(C)C.O>[OH:25][C:24]1[C:23]([CH3:26])=[CH:22][C:19]([CH2:20][CH2:8][C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:4]=2)=[O:9])=[CH:18][C:17]=1[CH3:16]
Reactant: CC(=O)c1cc(-c2ccccc2)c(C)s1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1O
Reaction time: 6 h
Yield: 52.9 %

Procedure:
A solution of 1-(5-methyl-4-phenyl-thiophen-2-yl)-ethanone (419 mg, 1.94 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (350 mg, 2.33 mmol) in ethanol (4 mL) and 5 N HCl in isopropanol (2 mL) is stirred at it for 1 h. The dark green solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in ethanol (10 mL) and treated with Pd/C (60 mg, 10% Pd). The slurry is hydrogenated under 1.4 bar of H2 for 6 h. The mixture is filtered, the solvent is removed in vacuo and the crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-methyl-4-phenyl-thiopen-2-yl)-propan-1-one (360 mg) as a colourless resin; LC-MS: tR=1.09 min, [M+1]+=351.25; 1H NMR (CDCl3): δ 7.60 (s, 1H), 7.46-7.30 (m, 5H), 6.85 8s, 2H), 4.48 (s, 1H), 3.14 (dd, J=7.0, 8.2 Hz, 2H), 2.92 (dd, J=7.0, 8.2 Hz, 2H), 2.52 (s, 3H), 2.21 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49]>ClCCl>[Br:49][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[CH:5][C:6]=1[Cl:10]
Reactant: O=C(c1ccc(-c2cc(Cl)c(CO)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(CBr)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Yield: 53.7 %

Procedure:
Dissolve (3′,5′-Dichloro-4′-hydroxymethyl-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone (13 g, 1 eq.) in dichloromethane (200 mL) and cool to 0° C. Add triphenylphosphine (12.2 g, 1.5 eq.) followed by carbon tetrabromide (15.4 g, 1.5 eq.) in portions. Filter the reaction mixture and concentrate the filtrate. Chromatograph the filtrate on silica gel to afford 8.0 g (54% yield) of the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].C(N(CC)CC)C.Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:24]=[C:23]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:25]2[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:21][N:22]=[C:23]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[CH:36][CH:37]=3)[N:24]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1cccc(C(=O)OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 120 °C
Yield: 57.3 %

Procedure:
To a nitrogen de-gassed solution of methyl 3-ethynylbenzoate (I31) (0.105 g, 0.655 mmol) in dry DMF (6 mL) were added triethylamine (0.308 mL, 2.18 mmol) followed by tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.250 g, 0.546 mmol), triphenylphosphine (0.021 g, 0.082 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.038 g, 0.055 mmol) and Cu(I)I (0.016 g, 0.082 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I32) (0.182 g, 57% yield) as an orange solid; 1H NMR (400 MHz, d6-DMSO) δ 10.28 (brs, 1H), 8.78 (s, 1H), 8.16-8.03 (m, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.55 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 3.90 (s, 3H), 3.50-3.41 (m, 4H), 3.11-2.99 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.82 min; m/z 582.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:58])[CH2:4][NH:5][C:6](=[O:57])[C@H:7]([NH:11][C:12](=[O:56])[C@H:13]([NH:21][C:22](=[O:55])[C@H:23]([NH:25][C:26](=[O:54])[CH2:27][C@@H:28]([OH:53])/[CH:29]=[CH:30]/[CH2:31][CH2:32][S:33][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]([CH3:10])[CH3:9].[Li+].[OH-].C(Cl)(Cl)Cl.Cl>C1COCC1.O>[OH:53][C@@H:28](/[CH:29]=[CH:30]/[CH2:31][CH2:32][S:33][C:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:27][C:26]([NH:25][C@H:23]([CH3:24])[C:22]([NH:21][C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:12]([NH:11][C@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([NH:5][CH2:4][C:3]([OH:58])=[O:2])=[O:57])=[O:56])=[O:55])=[O:54]
Reactant: COC(=O)CNC(=O)[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCC(=O)O
Yield: 42.4 %

Procedure:
To a solution of 13 (190 mg, 0.236 mmol) in THF (4 mL) was added a solution of LiOH (8.48 mg, 0.354 mmol) in H2O (1 mL) at 0° C. After stirring for 1 h CHCl3 (60 mL) was added to the solution followed by 1M HCl (10 mL). The layers were separated and the aqueous phase washed with CHCl3 (2×10 mL). The organic layers were combined, washed with brine, dried with MgSO4 and concentrated in vacuo. The crude material was then purified by flash column chromatography on silica gel (eluent 2% MeOH/CH2Cl2) to give 14 (80 mg, 0.1 mmol, 43%) as a pale yellow solid: Rf 0.21 AcOH/MeOH/CH2Cl2/(1:4:95).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[N:10][C:11]1(C)[C:16](=O)O[C:14](C)([CH3:18])[O:13][C:12]1=[O:20].[Na].O>C(O)C>[CH2:14]([O:13][C:12](=[O:20])/[C:11](=[N:10]/[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])/[CH3:16])[CH3:18]
Reactant: CC1(C)OC(=O)C(C)(N=Nc2ccc(F)cc2Br)C(=O)O1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C(C)=N/Nc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cooled (ice-bath) suspension of 126 g 5-(2-Bromo-4-fluoro-phenylazo)-2,2,5-trimethyl-[1,3]dioxane-4,6-dione in 550 ml ethanol was added a solution of 7.8 g sodium in 200 ml ethanol. The mixture was stirred 5 h at room temperature, poured into 200 ml water and the organics extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The resulting orange oil solidified upon drying under vacuum to afford the title compound. Yield:102 g. ISP-MS: m/e 303.2 ([M+H]+).
Reaction SMILES: C(O)C.CO.C([N:9]1[CH2:13][CH2:12]/[C:11](=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)/[C:10]1=[O:29])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:28][O:27][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1)/[CH:14]=[C:11]1/[C:10](=[O:29])[NH:9][CH2:13][CH2:12]/1
Reactant: COc1cc(/C=C2\CCN(C(C)=O)C2=O)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCNC2=O)ccc1-n1cnc(C)c1
Yield: 72 %

Procedure:
A mixed solution of ethanol (100 mL) and methanol (100 mL) of (E)-1-acetyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]pyrrolidin-2-one (7.5 g) and potassium carbonate (1.6 g) was agitated at room temperature for 2 hours. After condensing reaction solution to ⅓, added to iced water and ethyl acetate and deposited solids were separated by filtration to obtain 4.7 g of the title compound. Furthermore, the filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate after washed with a saturated saline solution. This solution was concentrated and the deposited solids was obtained by filtration to yield 2.7 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH:19]=O)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26]([NH2:30])(=[O:29])[CH2:27][CH3:28].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:22]([F:24])([F:25])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH2:19][NH:30][C:26](=[O:29])[CH2:27][CH3:28])=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C=O
Reactant: CCC(N)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCC(=O)NCc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 49.7 %

Procedure:
A mixture of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carbaldehyde (120 mg), propionamide (66 mg), trifluoroacetic acid (68 μl) and triethylsilane (144 μl) in toluene (2 ml) is refluxed overnight. After 20 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-ylmethyl}-propionamide (68 mg, compound 1.5 in Table 1) as a white foam. MS (HPLC/MS): 465 (MH+). Retention time: 1.98 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[NH2:13][C:14]1[C:19](Br)=[CH:18][CH:17]=[CH:16][N:15]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:19]2[C:14]([NH2:13])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1ncccc1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cl)cc1-c1cccnc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.6 %

Procedure:
The 300 mL round bottom flask, equipped with magnetic stirrer and refluxed condenser, was charged with 5-chloro-2-methoxyphenylboronic acid (5.00 g, 33 mmol), 2-amino-3-bromopyridine (5.70 g, 33 mmol), Pd2(dba)3 (604 mg, 2 mol %), 2-dicylohexylphosphino-2′,6′-dimethoxybiphenyl (542 mg, 4 mol %), potassium phosphate tribasic monohydrate (22.8 mg, 3 eq) and 100 mL of toluene. The flask was filled with nitrogen, and the reaction mixture was heated to reflux and stirred under nitrogen atmosphere for 24 hours. Then reaction was cooled down to room temperature, filtered through silica plug and evaporated. The residue was subjected to column chromatography on silica gel, eluent hexane/ethyl acetate mixture 1:1, providing 5.0 g of 3-(5-chloro-2-methoxyphenyl)pyridin-2-amine as yellow solid. The structure was confirmed by NMR and MS spectroscopy.
Reaction SMILES: [OH-].[K+].S([N:13]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([NH:27]S(C3C=CC(C)=CC=3)(=O)=O)[CH:25]=2)[CH2:20][C:19]2[CH:18]=[CH:17][C:16]([NH2:38])=[CH:15][C:14]1=2)(C1C=CC(C)=CC=1)(=O)=O.Br[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].S(=O)(=O)(O)O.[OH-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C.C(O)(=O)C.O>[CH2:40]([NH:38][C:16]1[CH:17]=[CH:18][C:19]2[C:14]([CH:15]=1)=[N:13][C:26]1[C:21](=[CH:22][CH:23]=[C:24]([NH:27][CH2:16][CH2:15][CH2:14][CH2:19][CH2:18][CH3:17])[CH:25]=1)[CH:20]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3c(c2)N(S(=O)(=O)c2ccc(C)cc2)c2cc(N)ccc2C3)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCNc1ccc2cc3ccc(NCCCCCC)cc3nc2c1
Temperature: 60 °C
Reaction time: 22 h

Procedure:
298 mg of ground potassium hydroxide are added to a solution of 500 mg of N,N'-bistosyl-3,6-diaminoacridine and 797 mg of 1-bromohexane in 25 ml of dimethylformamide, and the mixture is stirred at 60° C. for 22 hours. The cooled reaction mixture is subsequently poured into water and extracted with ethyl acetate, and the organic phase is separated off, washed with aqueous NaCl solution and then dried over sodium sulfate. Evaporation gives a dark-red oil, which is taken up in toluene/ethyl acetate (20:1) and chromatographed on silica gel. Evaporation of the solvent gives a yellow, viscous oil, which is dissolved in 11.5 ml of glacial acetic acid, 4.6 ml of 97% sulfuric acid are added with water cooling, and the mixture is then stirred at room temperature for 15 hours. The red reaction mixture is poured into ice water and adjusted to pH 11 by means of 30% NaOH. The mixture is extracted with ethyl acetate, and the organic phase is washed with 2N HCl and saturated aqueous NaCl solution and then dried over sodium sulfate. After evaporation, the dark-red, viscous oil is taken up in t-butyl methyl ether/methanol (5:1) and chromatographed on silica gel, giving the title compound as orange-red crystals having a melting point of >200° C. (decomposition). 1H-NMR (CDCl3): 8.1 [s, 1H, C(9)]; 7.44 [d, 2H, C(8)]; 6.93 [s, 2H, C(S)]; 6.82 [d, 2H, C(7)]; 3.20 [t, 4H, N-CH2 ]; 1.68 [m, 6H, CH3 ].
Reaction SMILES: [CH2:1]([N:8]1[C:16]([OH:17])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C1COCC1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]([O:17][C:36]([O:38][CH3:39])=[O:37])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1nc(O)n2Cc1ccccc1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Oc1nc2c(N)ncnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
241 mg (1 mmol) of 9-benzyl-8-hydroxyadenine was dissolved in 20 ml of anhydrous THF. To this solution, 202 mg (2 mmol) of triethylamine and 111 mg (0.5 mmol) of dimethylaminopyridine were added and stirred for 1 hr at room temperature. To the resultant mixture, 113 mg (1.2 mmol) of methyl chloroformate was added and stirred overnight at room temperature. 50 ml each of ethyl acetate and water were added thereto for extraction. After the organic layer was removed by vacuum distillation, 20 ml of ether was added to the residue. Then, crystals were collected by filtration (300 mg; yield: 100%).