Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]#[C:17][NH2:18]>Cl.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][C:17]([NH2:18])=[NH:16])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(OCc2ccccc2)c1
Temperature: 120 °C
Yield: 37.3 %

Procedure:
3-benzyloxy aniline (1 g, 5 mmol) and cyanamide (420 mg, 10 mmol) were dissolved in 4 mL of 4N HCl in dioxane and heated to 120° C. overnight. The reaction mixture was cooled to room temperature, quenched with water, and extracted with diethyl ether. The aqueous layer was made basic with 2N NaOH and extracted thrice with dichloromethane. The organic extracts were combined and washed with brine, dried over MgSO4, and concentrated to afford 4 (450 mg) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[CH3:29][C:30]([S@:33]([NH2:35])=[O:34])([CH3:32])[CH3:31].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CO>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][C:2]1[CH:3]=[C:4]([CH:26]([NH:35][S@:33]([C:30]([CH3:32])([CH3:31])[CH3:29])=[O:34])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: CC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(N[S@@](=O)C(C)(C)C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
1-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanone (0.48 g, 1.2 mmol) was added to a solution of (R)-(+)-2-methyl-2-propanesulfinamide ((0.150 g, 1.2 mmol), titanium (iv) ethoxide (0.510 mL, 2.48 mmol) in THF (5 mL). The reaction mixture was heated to 70° C. for 2 h at which point additional (R)-(+)-2-methyl-2-propanesulfinamide (0.150 g, 1.2 mmol) and titanium (iv) ethoxide (0.51 mL, 2.48 mmol) were added and the reaction mixture was allowed to stir for 18 h at 70° C. The reaction mixture was cooled to ambient temperature and then to −50° C. To the reaction mixture was added dropwise 1 M solution of L-Selectride (3.7 mL, 3.7 mmol) also at −50° C., and allowed to stir for 5 h at −50° C. The reaction mixture was warmed to 0° C. and MeOH was added dropwise until gas evolution was no longer observed. The crude reaction mixture was poured into an equal volume of brine while being stirred rapidly. The resulting suspension was filtered through a plug of celite, the cake rinsed with EtOAc and MeOH. The filtrate was reduced in vacuo, the residue diluted with EtOAc, extracted with brine and dried over MgSO4. The crude reaction mixture was concentrated in vacuo and purified by silica gel chromatography to afford (S)-N-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethyl)-2-methylpropane-2-sulfinamide. MS (ESI) m/z: calculated: 493.2; Observed: 494.0 (M++1).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([C:21]#[CH:22])([O:16][C:17](=[O:20])[NH:18][CH3:19])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>[O-]CC.[Na+]>[C:23]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([O:16][C:17](=[O:20])[N:18]([CH3:19])[C:21]3=[CH2:22])[CH2:12][CH2:11]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#CC1(OC(=O)NC)CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Product: C=C1N(C)C(=O)OC12CCN(CC=C(c1ccccc1)c1ccccc1)CC2
Yield: 71.7 %

Procedure:
9.4 g of 1-(3,3-diphenyl-2-propenyl)-4-ethynyl-4-methylcarbamoyloxypiperidine are refluxed in 100 ml of 0.05 mol/liter ethanolic sodium ethoxide solution under argon for 3 hours. After cooling down, the alkoxide is decomposed by adding aqueous ammonium chloride solution and the solvent is distilled off under reduced pressure. After adding benzene and water to the residue, the benzene layer is separated and dried, then evaporated under reduced pressure. After recrystallizing the solid evaporation residue from ethanol, the title compound is obtained in 71.7% yield, m.p.: 126°-127° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1B(O)O>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH:13]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Cl)ccc2Cl)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 2,5-dichloro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.97-1.08 (m, 6H), 1.59 (dd, J=13.33, 6.72 Hz, 1H), 1.78 (dt, J=13.76, 6.94 Hz, 1H), 2.04 (dd, J=13.45, 7.34 Hz, 1H), 3.85 (t, J=7.70 Hz, 1H), 7.39-7.87 (m, 10H); Calcd for C25H21Cl2F302 (M+Na) 503.09, Found 503.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]1=[O:20].[C:21]1([NH2:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[C:21]1([NH:27][S:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:20])[CH:4]=[C:5]3[C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:13])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)cc(C(F)(F)F)c2cc(S(=O)(=O)Nc3ccccc3)ccc21
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution of 1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 1, 65 mg, 200 μmol) in anhydrous DMF (1.5 mL) was contacted with PhNH2 (19 μL, 210 μmol), employing pyridine (17 μL, 220 μmol) as base), before being stirred overnight under N2. The reaction mixture was diluted with EtOAc (70 mL), before being washed with H2O (30 mL), 1 M HCl (30 mL), H2O (30 mL), saturated aqueous NaHCO3 (30 mL), H2O (30 mL), & brine (30 mL). After drying (MgSO4), the organic phase was filtered & concentrated to give a residue that was recrystallised from EtOAc-PE to furnish the title compound (39 mg, 50%): δH ((CD3)2SO)=3.60 (s, 3H), 7.00 (s, 1H), 7.10 (d, 2H), 7.15–7.20 (m, 3H), 7.80 (d, 1H), 8.00–8.05 (m, 2H); m/z (ES+)=383.1 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH:16]([C:19]1[C:24](/[CH:25]=[CH:26]/[CH:27]=[O:28])=[C:23]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]([CH:36]=[N:37][O:38][CH3:39])=[C:21]([CH:40]([CH3:42])[CH3:41])[N:20]=1)([CH3:18])[CH3:17]>O1CCCC1.CCCCCC.O.C(O)(=O)C>[CH:16]([C:19]1[C:24](/[CH:25]=[CH:26]/[CH:27]([OH:28])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:23]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:22]([CH:36]=[N:37][O:38][CH3:39])=[C:21]([CH:40]([CH3:42])[CH3:41])[N:20]=1)([CH3:17])[CH3:18]
Reactant: CON=Cc1c(C(C)C)nc(C(C)C)c(/C=C/C=O)c1-c1ccc(F)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CON=Cc1c(C(C)C)nc(C(C)C)c(/C=C/C(O)CC(=O)CC(=O)OC)c1-c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
0.18 ml (1.65 mmol) of methyl acetoacetate in 5 ml of dry tetrahydrofuran are added dropwise at -5° C. under nitrogen to a suspension of 67 mg (2.2 mmol) of 80% pure sodium hydride in 10 ml of dry tetrahydrofuran. After 15 min, 1.01 ml (1.65 mmol) of 15% strength butyllithium in n-hexane are added dropwise at the same temperature and the mixture is then stirred for 15 minutes. 410 mg (1.1 mmol) of the compound from Example 4, dissolved in 10 ml of dry tetrahydrofuran, are then added and the mixture is stirred at -5° C. for 30 minutes. 0.3 ml of glacial acetic acid is cautiously added to the reaction solution, it is diluted with 100 ml of water and the mixture is extracted 3 times with 100 ml of ether each time. The combined organic phases are washed twice with saturated sodium hydrogencarbonate solution, dried over magnesium sulphate and concentrated in vacuo. The residue is filtered through silica gel (solvent: ethyl acetate/ petroleum ether 1:1).
Reaction SMILES: C([O-])(=O)CO.[NH2:6][C:7]1[NH:11][N:10]=[C:9]([CH2:12][OH:13])[N:8]=1.[CH3:14][C:15](=O)[CH2:16][C:17](=O)[CH3:18].C(O)(=O)C>C(Cl)Cl.CCO>[CH3:14][C:15]1[CH:16]=[C:17]([CH3:18])[N:11]2[N:10]=[C:9]([CH2:12][OH:13])[N:8]=[C:7]2[N:6]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])CO
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a 2 L, 3-neck flask was charged glycolate salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol (99.93 g, 0.526 mol), 2,4 pentanedione (0.578 mols, 60 mL), acetic acid (6.70 mL), and EtOH (550 mL). The mixture was heated to a slight reflux. One hour after adding the reagents, the resulting solution was cooled to ambient temperature, and CH2Cl2 (500 mL) and Celite (25.03 g) were added. After stirring for 1 h, the mixture was filtered through a 4″ Buchner funnel packed with celite (20 g) and rinsed with EtOH (100 mL). The solution was distilled to 5 vols then cooled to 0° C. for 1-2 hours. The slurry was filtered and the cake was rinsed with cold EtOH (2×100 mL). The solids were dried to provide 76.67 g (81.7%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:25]([O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:26].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.CN(C=O)C>[CH2:25]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[O:5])[CH2:30][CH2:29]1)[CH3:26]
Reactant: CCOC1CCNCC1
Reactant: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)O)c3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc(OC)c34)ccc2F)CC1
Yield: 74.6 %

Procedure:
2-fluoro-5-((8-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (125) (200 mg, 0.61 mmol) and 4-ethoxypiperidine (79 mg, 0.61 mmol) were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.163 mL, 0.91 mmol) and then HBTU (347 mg, 0.91 mmol). The solvent was then removed to give a brown solid, which was dissolved in acetonitrile. A white solid precipitated, which was filtered and dried to afford the desired material as a white crystalline solid (200 mg, 74.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 1.46-1.62 (1H, m), 1.63-1.82 (2H, m), 1.87-1.96 (1H, m), 3.07-3.18 (1H, m), 3.43-3.59 (5H, m), 3.77-3.82 (3H, m), 3.99-4.11 (1H, m), 4.45 (2H, s), 6.91-7.02 (1H, m), 7.11-7.28 (3H, m), 7.62-7.71 (1H, m), 8.03-8.08 (1H, m), 10.29 (1H, s); m/z (ES+) (M+H)+=440.41; HPLC RT=1.87 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[C-:20]#[N:21].[Na+]>CCO>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[N:7]=[CH:8][C:3]([CH2:2][C:20]#[N:21])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(Oc2ccc(CCl)cn2)cc1
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Oc2ccc(C(F)(F)F)cc2)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a solution of 5-chloromethyl-2-(4-trifluoromethylphenoxy)-pyridine (1.8 g, 6.27 mmol) in EtOH (12 mL) was added NaCN (1.23 g, 25 mmol). The reaction mixture was heated to 50° C. for 16 h. More ethanol (6 mL) was added, and the reaction mixture clarified. After an additional 3 h, the solvent was removed in vacuo, the residue taken up in Et2O and washed with H2O. The organic layer was dried with Na2SO4, suction filtered and concentrated in vacuo. The residue was purified by flash chromatography (50% Et2O in petroleum ether over SiO2) to yield [6-(4-trifluoromethylphenoxy)-pyridin-3-yl]-acetonitrile (1.3 g) as a pink solid; 1H NMR (300 MHz, CDCl3) δ 8.17-8.09 (m, 1H), 7.81-7.71 (m, 1H), 7.70-7.61 (m, 2H), 7.29-7.19 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 3.73 (s, 2H); EIMS m/z 278 ([M]+).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4](C)C.[F:10][CH2:11][CH:12]([O:15][C:16]1[CH:17]=[C:18]([O:31][C:32]2[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=2)[CH:19]=[C:20]([C:22]([NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)=[O:23])[CH:21]=1)[CH2:13][F:14].Cl.N1CCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:3]1([C:38]([C:35]2[N:36]=[CH:37][C:32]([O:31][C:18]3[CH:19]=[C:20]([CH:21]=[C:16]([O:15][CH:12]([CH2:13][F:14])[CH2:11][F:10])[CH:17]=3)[C:22]([NH:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)=[O:23])=[N:33][CH:34]=2)=[O:39])[CH2:4][CH2:9][CH2:7]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)cn3)cc(OC(CF)CF)c2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(OC(CF)CF)c2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.5 %

Procedure:
DIPEA (0.45 mL, 2.58 mmol) was added to a mixture of 5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylic acid (0.28 g, 0.65 mmol), azetidine hydrochloride (121 mg, 1.29 mmol) and HATU (516 mg, 1.36 mmol) in DMF (5 mL) and stirred at RT for 72 hours. Ethyl acetate (40 mL) was added and the organics washed with water (2×30 mL), brine (30 mL), dried (MgSO4), filtered and reduced in vacuo to give a yellow oil which was chromatographed on silica, eluting with 0-100% ethyl acetate in isohexane, to give the desired compound (109 mg). 1H NMR δ (CDCl3): 2.32 (quin, 2H), 3.70 (s, 3H), 4.19 (t, 2H), 4.54-4.72 (m, 7H), 6.73 (s, 1H), 6.93 (t, 1H), 7.22 (d, 1H), 7.25 (s, 1H), 7.34 (s, 1H), 8.28 (d, 1H), 8.78 (d, 1H), 8.80 (s, 1H); m/z 473 (M+H)+
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[N:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:32][CH:33]=2)O1.CN(C)C(=O)C>C(OCC)(=O)C.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>[CH3:11][C:9]1[N:8]=[CH:7][N:6]2[C:2]([C:32]3[CH:31]=[C:30]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:29]=[CH:28][CH:33]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Cc1cc2ncc(Br)n2cn1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc2ncc(-c3cccc(-c4ccccc4C#N)c3)n2cn1
Temperature: 80 °C
Yield: 49 %

Procedure:
A stirred mixture of 3-bromo-7-methylimidazo[1,2-c]pyrimidine (0.1013 g, 0.478 mmol), dried potassium phosphate (0.2027 g, 0.955 mmol) and a 0.5 M solution of 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile in N,N-dimethylacetamide (1.91 ml, 0.955 mmol) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (28.7 mg, 0.0248 mmol) was then added and the mixture was degassed with two more evacuation-refilling cycles before heating at 80° C. under nitrogen for 45 h, adding more dried potassium phosphate (0.0503 g, 0.237 mmol), a 0.5 M solution of 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile in N,N-dimethylacetamide (0.48 ml, 0.240 mmol) and tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.0069 mmol) after 21 h with degassing. The mixture was diluted with ethyl acetate and filtered through glass fibre filter paper, washing solid with more ethyl acetate. The combined filtrates were washed with saturated aqueous NaCl (15 ml), and the aqueous layer was further extracted with ethyl acetate (2×25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc) to give 72.8 mg (49%) of the title compound as a yellow-brown solid: mp 119° C. (softens) (CH2Cl2-EtOAc-isohexane); 1H NMR (400 MHz, CDCl3) δ 2.57 (3H, s), 7.36 (1H, s), 7.51 (1H, td, J 7.6, 1.2 Hz), 7.57-7.72 (6H, m), 7.78 (1H, fine m), 7.82 (1H, dd, J 7.5, 1.4 Hz), 9.34 (1H, s); MS (ES+) m/z 311 [M+H]+; Anal. Found: C, 71.93; H, 4.68; N, 16.35%. Required for C20H14N4.1.4H2O: C, 71.58; H, 5.05; N, 16.70.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]3[C:19](=[O:22])[O:20][CH2:21][C:9]2=3)=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[N:11]=[C:10]3[C:19](=[O:22])[O:20][CH2:21][C:9]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(C)NC2=C(COC2=O)C1c1ccc(Cl)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1c(C)nc2c(c1-c1ccc(Cl)cc1)COC2=O

Procedure:
Corresponding to Example 1, 1.5 g (3.92 mmol) of methyl 1,4,5,7-tetrahydro-4-(4-chlorophenyl)-2-methyl-7-oxo-furo[3,4-b]-pyridine-3-carboxylate in 350 ml of methylene chloride are reacted with 7.5 g of manganese dioxide to give 0.94 g (63% of theory) of the title compound.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH3:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.Cl>CO.C(OCC)C>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH:25][CH3:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CN(Cc1ccccc1Sc1ccc2c(ccn2C(=O)OC(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CNCc1ccccc1Sc1ccc2[nH]ccc2c1
Yield: 10.4 %

Procedure:
(2-Mercapto-benzyl)-methyl-carbamic acid tert-butyl ester (1.85 g, 7.30 mmol) in dry toluene (15 mL) is placed in an Emrys Optimizer EXP 20 mL tube. Tris(dibenzylideneacetone) dipalladium (334 mg, 0.37 mmol), bis(2-diphenylphosphinophenyl)ether (197 mg, 0.37 mmol), tert-butyl-5-bromoindole-1-carboxylate (2.38 g, 8.03 mmol) and potassium tert-butoxide (860 mg, 7.67 mmol) are added. The reaction vessel is sealed and subjected to microwave heating at 160° C. for 15 minutes. Upon cooling the mixture is poured onto a plug of silica and the product is eluted with ethyl acetate-heptane (1:4). 0.67 g (20%) of 5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylic acid tert-butyl ester is isolated and used in the next step whithout further purification. 5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylic acid tert-butyl ester (0.67 g, 1.43 mmol) in methanol (15 mL) and diethyl ether saturated with hydrochloric acid (15 mL) is stirred at room temperature for 1 hour and concentrated in vacuo. Ice/water is added to the remanence and 28% aqueous NaOH is added until pH 9. The aqueous fraction is extracted with ethyl acetate (3×15 mL). Combined organic fractions are dried with MgSO4 and concentrated in vacuo. The product is purified by silica gel chromatography eluting with ethyl acetate-triethyl amine (100:4) followed by ethyl acetate-ethanol-triethyl amine (100:5:5). Upon evaporation of the volatiles, 40 mg (10%) of [2-(1H-indol-5-ylsulfanyl)-benzyl]-methyl-amine is isolated.
Reaction SMILES: C([O:4][C:5](=[O:38])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[O:22][CH:21]3[CH:23]([CH2:36][OH:37])[O:24][CH:25]([N:26]4[CH:34]=[N:33][C:32]5[C:27]4=[N:28][CH:29]=[N:30][C:31]=5[Cl:35])[CH:20]3[O:19]2)=[CH:14][CH:13]=1)C=C.CC1(C)CC(=O)CC(=O)C1>C(Cl)Cl.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>[Cl:35][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[C:32]=1[N:33]=[CH:34][N:26]2[CH:25]1[CH:20]2[CH:21]([O:22][CH:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:38])=[O:4])=[CH:17][CH:16]=3)[O:19]2)[CH:23]([CH2:36][OH:37])[O:24]1
Reactant: C=CCOC(=O)CCCCCOc1ccc(C2OC3C(CO)OC(n4cnc5c(Cl)ncnc54)C3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: ClCCl
Product: O=C(O)CCCCCOc1ccc(C2OC3C(CO)OC(n4cnc5c(Cl)ncnc54)C3O2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84.8 %

Procedure:
A mixture of 5 (59.31 g, 108.8 mmol), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 12.6 g, 10.9 mmol), and dimedone (45.7 g, 326.4 mmol) in dry DCM (600 mL) was stirred in a nitrogen atmosphere for 3.5 h at room temperature. 500 ml of the solvent was removed in vacuo and the remaining volume was loaded on a silica plug. After the dimedone byproducts were removed by washing the plug with MeOH/DCM 1:100, the product was eluted with MeOH/DCM 1:10. The fraction containing the product was concentrated in vacuo to afford 6 as a white powder (46.6 g, 92.3 mmol, 85%) as a mixture of two diastereomers: M.p.: 127-129° C.; 1H-NMR (400 MHz, CDCl3) δ=11.50 (s, 1H, 1H′), 8.79 (s, 1H), 8.78 (s, 1H′), 8.42 (s, 1H), 8.34 (s, 1H′), 7.47 (d, J=8.6, 2H), 7.37 (d, J=8.6, 2H′), 6.95 (d, J=8.5, 2H), 6.90 (d, J=8.5, 2H′), 6.24 (s, 1H), 6.19 (m, 1H, 1H′), 6.02 (s, 1H′), 5.37-5.19 (m, 2H, 2H′), 4.73 (s, 1H, 1H′), 4.57 (m, 1H, 1H′), 4.04-3.86 (m, 4H, 4H′), 2.40 (m, 2H, 2H′), 1.82 (m, 2H, 2H′), 1.72 (m, 2H, 2H′), 1.55 (m, 2H, 2H′); 13C-NMR (400 MHz, CDCl3) δ=178.8, 178.8, 160.6, 160.5, 152.3, 152.2, 150.6, 150.6, 133.4, 133.3, 132.2, 132.2, 128.3 (2C),128.1, 128.0 (2C), 127.6, 114.9, 114.9, 114.8 (2C), 114.7 (2C), 108.1, 105.1, 94.0, 92.0, 86.4, 86.3, 84.2, 83.5, 83.5, 80.5, 68.0, 67.9, 63.3, 63.0, 34.0, 34.0, 29.0, 29.0, 25.8, 25.8, 24.6, 24.6; IR (film) ν=3292, 3109, 3074, 2938, 1708, 1595, 1392, 1245, 1225, 1194, 1108, 1069, 828; HRMS (MALDI-FTMS) m/z 527.1285 (527.1304 calculated for C23H25N4O7ClNa (M+Na)+).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1C=CC=CC=1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:7]=1
Reactant: BrCCCCBr
Reactant: CC(C)(C)Oc1cccc(CO)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)Oc1cccc(COCCCCBr)c1
Temperature: 25 °C

Procedure:
To a solution of (3-tert-butoxy-phenyl) methanol (4.02 g, 0.022 mol) and tetrabutylammonium hydrogen sulfate (0.379 g, 0.00115 mol) in 50% NaOH solution (6 mL) and benzene (15 mL) Was added 1,4-dibromobutane (7.99 mL, 0.067 mol) with vigorous stirring at ambient temperature. After stirring for 8 h, the mixture was partitioned between H2O and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound after purification on an ISCO Combiflash eluting with 0-10% EtOAc/hexane.