Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][C@H:10]([C:8]2[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]3[CH:21]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][O:12][CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (69 mg, 0.24 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (37 mg, 0.24 mmol) and DIPEA (0.21 mL, 1.2 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-20% DCM in EtOAc) to afford 271 as a yellow solid (78 mg, 80%). LCMS (Method K): RT 3.52 min [M+H]+ 405.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.68-8.64 (1H, m), 8.11 (1H, td, J=7.76, 1.94 Hz), 7.84 (1H, s), 7.79-7.73 (2H, m), 7.66 (1H, d, J=7.94 Hz), 7.56 (1H, ddd, J=7.52, 4.87, 0.98 Hz), 7.30-7.13 (4H, m), 6.03-5.95 (1H, m), 3.83 (2H, d, J=6.59 Hz), 3.19 (3H, s)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[C:4]([OH:13])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(#N)C>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:13][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=[C:2]([Br:1])[CH:3]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1CCCc2c(O)cc(Br)cc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1cc(Br)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a suspension of 7-bromo-5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (XIb, 158 mg, 0.65 mmol) and cesium carbonate (431 mg, 1.31 mmol) in acetonitrile (5 mL) was added tert-butyl bromoacetate (XII, 261 mg, 1.31 mmol) at room temperature under nitrogen. The resulting suspension was stirred for 15 h at room temperature and then concentrated under vacuum. The residue was diluted with water (10 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL), and the combined organic extracts were washed with brine solution (50 mL), then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. Chromatography using an ISCO (40 g) column, (gradient elution with 5-25% ethyl acetate in hexanes) provided (3-bromo-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (150 mg, 64%) as a white solid: ES(+)-HRMS m/e calcd. for C16H19O4Br (M+Na)+377.0359, obsd. 377.0358.
Reaction SMILES: Br[C:2]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH:3]=1.C([Li])CCC.B(F)(F)F.[CH3:21][CH2:22][O:23]CC.C1OC1.[Cl-].[NH4+]>O1CCCC1>[O:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH:3]=[C:2]1[CH2:21][CH2:22][OH:23]
Reactant: CCOCC
Reactant: BrC1=COc2ccccc2O1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CO1
Solvent: C1CCOC1
Product: OCCC1=COc2ccccc2O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
3.73 g (17.5 mmol) of the compound obtained in Step A are dissolved in 90 ml of anhydrous tetrahydrofuran; the mixture is then cooled to −78° C. 16.4 ml (26.25 mmol) of n-butyllithium (1.6 M/hexane) are then slowly added to the solution; the reaction mixture is then stirred for 2 hours under argon at the same temperature. 2.2 ml (17.5 mmol) of boron trifluoride etherate and an excess of ethylene oxide are added in succession to the solution. After 30 minutes of stirring at −78° C., the reaction mixture is hydrolysed with a saturated ammonium chloride solution; the aqueous phase is then extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. The title alcohol is obtained pure in the form of a clear oil after passage over a silica column (eluant:AcOEt/PE:20/80).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][C:5]=1[CH3:18])(=[O:3])[CH3:2].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCCCC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:5]1[CH:6]=[C:7]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=2)[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 80 °C
Yield: 96 %

Procedure:
To an ambient temperature solution of trifluoro-methanesulfonic acid 4-acetyl-3-methyl-phenyl ester (6.10 g, 21.61 mmol) in dioxane/water (150/30 mL) is added 4-(trifluoromethyl)phenylboronic acid (4.51 g, 23.77 mmol), potassium carbonate (4.48 g, 32.42 mmol) and the reaction mixture is degassed with nitrogen for 20 min. Tetrakis(triphenylphosphine)palladium (1.25 g, 1.08 mmol) is added and the reaction mixture is heated to 80° C. overnight. TLC (10% EtOAc/hexane) indicates complete consumption of starting material. The reaction mixture is concentrated and chromatographed (330 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (5.77 g, 96%). 1NMR (400 MHz, CDCl3) δ ppm: 7.82 (d, 1H, J=7.9 Hz), 7.72 (s, 4H), 7.51-7.46 (m, 2H), 2.63 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([NH:18][C:19]([CH:21]4[CH2:24][CH2:23][CH2:22]4)=[O:20])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH2:35])=[CH:30][CH:29]=2>>[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH:35][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][CH:15]([NH:18][C:19]([CH:21]5[CH2:24][CH2:23][CH2:22]5)=[O:20])[CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:30][CH:29]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1)C1CCC1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(NC(=O)C6CCC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-cyclobutanecarboxylic acid {1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 474 (MH+); HPLC Rf: 4.37 min.; HPLC purity 97%.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CI.[C:32](O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C.O.CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH3:32])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COC(=O)c1ccc(-c2ccccc2NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2N(C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under ice-cooling, 60% sodium hydride (0.21 g) was added to an N,N-dimethylformamide (15 mL) solution of methyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (1.3 g), followed by stirring at room temperature for 10 minutes. Then, methyl iodide (0.32 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. Water, a 10% aqueous solution of citric acid, and diethyl ether were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 1.1 g of methyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22](CC=C)[C@@:16]2([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][C@H:18]3[C:26]#[N:27])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN1C(=O)CC(=O)N(C)C1=O.[OH-].[Na+]>ClCCl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][C@H:18]3[C:26]#[N:27])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#C[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 32.5 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (64 mg, 0.055 mmol) was added to a stirred mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-cyano-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane (Example 55; 500 mg, 1.01 mmol), 1,3-dimethylbarbituric acid (465 mg, 3.0 mmol) in dichloromethane (10 ml) at room temperature. The reaction mixture was stirred at 30-35° C. for 90 minutes and treated with 2M aqueous NaOH (10 ml). The mixture was stirred for 5 minutes, then diluted with water (30 ml) and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 10-40%) to give the title compound (392 mg, 85%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([F:16])[CH:5]=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[C:4]([F:16])[CH:5]=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: N#Cc1ccccc1-c1cc(N)cc(F)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1cc(F)cc(Br)c1
Temperature: 3 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A warm solution of 5′-amino-3′-fluorobiphenyl-2-carbonitrile (4.5 g, 21 mmol) in 1,4-dioxane (20 mL) was treated with 48% hydrobromic acid (100 mL) and the resulting suspension stirred and cooled to 3° C. (internal temperature). A solution of sodium nitrite (1.7 g, 24 mmol) in water (4 mL) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before adding a cooled (5° C.) solution of copper(I) bromide (9.1 g, 3 mmol) in 48% hydrobromic acid (30 mL). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (500 mL) and extracted with ethyl acetate (2×200 mL). The organics were combined, washed with 5% aqueous sodium sulphite and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica gel. Purification on silica gel, eluting with isohexane (containing 1% methanol) on a gradient of ethyl acetate (5-15%) afforded 5′-bromo-3′-fluorobiphenyl-2-carbonitrile as a white solid (5.52 g, 94%).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].C([O-])(O)=O.[Na+].O1CCOCC1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>CCOC(C)=O.O>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([NH:5][NH:4][C:1](=[O:3])[CH3:2])=[O:23]
Reactant: CC(=O)NN
Reactant: O=C(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
To a mixture of acetic hydrazide (2.63 g) and NaHCO3 (3.44 g) in a solution of dioxane (40 ml) and H2O (4 ml) was added dropwise 2-thiophenecarbonyl chloride (4.00 g) with ice-cooling. After stirring for 2 hours at ambient temperature, the mixture was diluted with AcOEt and filtered. After concentration of the filtrate, the obtained residue was crystallized from a mixture of AcOEt and hexane to give 5.38 g of N-(2-thienylcarbonylamino)ethanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[CH:9]=O)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][NH:19][C:4]=2[CH:3]=1
Reactant: COc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c(C=O)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CNc1cc(Cl)ccc1O2
Yield: 48.9 %

Procedure:
5.00 g of 2-(4-chloro-2-nitrophenoxy)-5-methoxybenzaldehyde, prepared as described above in Example 1, in 50 mL of tetrahydrofuran (THF) was shaken in a Parr hydrogenator at 5 psi hydrogen with Raney nickel at 25° C. for 5 hours. The catalyst was filtered from the reaction and the solution evaporated in vacuo. The crude product was purified by column chromatography in the manner described by Still et al., "A Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution," J. Org. Chem, 43, 2923 (1978), through silica gel 60 using hexane:ethyl acetate (2:1) to yield 2.08 g (48.9%) of product as a white solid. Melting Point: 111°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][C:3]=1[CH3:12].CN.Cl.[BH3-][C:17]#[N:18].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:18][CH3:17])=[CH:4][C:3]=1[CH3:12]
Reactant: [BH3-]C#N
Reactant: Cc1cc(CCC=O)ccc1F
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCCCc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a solution of 3-(4-fluoro-3-methylphenyl)propanal (1.0 g, 6 mmol) in 20 mL MeOH was added MeNH2HCl (556 mg, 7.2 mmol) followed by NaBH3CN (452 mg, 7.2 mmol) at room temperature. The mixture was stirred for 2 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and the product isolated by flash column chromatography eluting with 0% to 10% MeOH/DCM to provide 461 mg of the title compound as an colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:10]1[CH:24]=[CH:23][C:13]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:12][C:11]=1[Cl:25])(=O)[CH3:8].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[C:50]([O-:53])(O)=O.[Na+]>C1COCC1>[Cl:25][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][C:10]=1[CH:7]([CH3:8])[CH:50]=[O:53])[O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1
Reactant: O=C([O-])O
Reactant: CC(=O)c1ccc(Oc2ccc(C#N)cc2)cc1Cl
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C=O)c1ccc(Oc2ccc(C#N)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (248 mg) was added to a solution 4-(4-acetyl-3-chloro-phenoxy)-benzonitrile (500 mg) and (methoxymethyl)-triphenylphosphonium chloride (694 mg) in THF (10 ml) at room temperature. The mixture was stirred for 1 h at room temperature. 25% aqueous HCl (4 ml) was added. The resulting mixture was stirred 1 h at room temperature and poured then carefully to a saturated aqueous NaHCO3 solution. After neutralization, the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2) to give the title compound (450 mg) as yellow oil. MS (m/e, ISP neg. ion)=284.3 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C:13](=[O:17])[N:14]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[CH2:15][CH2:16][C:11]=3[S:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1NCCc2scc(-c3ccc(F)cc3)c21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2scc(-c3ccc(F)cc3)c2C1=O
Yield: 17 %

Procedure:
Using analogous reaction conditions as described in Example 1, 3-(4-fluoro-phenyl)-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-15c: 150 mg, 0.61 mmol) was reacted with 3-iodo-4-methyl-pyridine (133 mg, 0.61 mmol), 1,4-dioxane (10 mL), copper iodide (11.6 mg, 0.061 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (25.98 mg, 0.183 mmol) and potassium phosphate (323.3 mg, 1.525 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 35 mg of the product (17.5% yield).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16].C([S-])CC.[Na+]>CN(C=O)C>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCCOc1cc(C=O)ccc1OC
Agent: CCC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
4-methoxy-3-(3-methoxypropoxy)benzaldehyde (22 g, 98 mmol) was dissolved in DMF (490 mL) and sodium propanethiolate (12.5 g, 127 mmol) was added. The mixture was brought to 100° C. and the reaction mixture was stirred for 30 minutes. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in dichloromethane (200 mL) and saturated aqueous ammonium chloride (200 mL). Hydrochloric acid 1N was then added until acidic pH. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to yield 20 g (quantitative yield) of the desired product as a yellow oil, used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]=1[NH2:26])=[CH:17][CH:16]=[CH:15][CH:14]=2>C(O)C>[C:1]1([C:7]2[CH:9]=[N:26][C:25]3[C:12](=[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]4=[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]4=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: Nc1c(N)c2ccccc2c2ccccc12
Solvent: CCO
Product: c1ccc(-c2cnc3c4ccccc4c4ccccc4c3n2)cc1
Yield: 92 %

Procedure:
First, 2.16 g of phenylglyoxal and 3.36 g of 9,10-diaminophenanthrene were dissolved in a solvent of 100 mL of dehydrated ethanol under a nitrogen atmosphere. The solution was refluxed for 7 hours to be reacted. The white power precipitated through the reaction was filtered. The residue was washed with ethanol and then ether to give a dibenzo[f,h]quinoxaline derivative, Hdbq-P, which was the target substance (yield: 92%). Synthesis scheme of Step 1 is shown in (a-1) below.
Reaction SMILES: [CH3:1][CH:2]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>ClCCl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:9]([CH:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:27])=[CH:21][CH:20]=1
Reactant: CC(NC1CCN(C)CC1)c1ccccc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(CC(=O)N(C2CCN(C)CC2)C(C)c2ccccc2)cc1
Reaction time: 16 h
Yield: 69.9 %

Procedure:
47AKU-36 (218 mg, 1.0 mmol) was dissolved in 10 ml dichloromethane and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40° C.). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 256 mg (70%) 47AKU-37. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.5. HPLC-MS (Method A): M+=367.3 (UV/MS (%)=100/99).
Reaction SMILES: Br[C:2]1[C:3]([OH:25])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:8]=[CH:7]2.[CH3:26][NH:27][CH2:28][CH2:29][OH:30]>[Cl-].[NH4+]>[OH:25][C:3]1[C:2]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:5][CH:4]=1
Reactant: CNCCO
Reactant: CC(Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@@H](Cn1ncc2ccc(O)c(N(C)CCO)c21)NC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 68 %

Procedure:
To a stirred solution of the product from Step A (0.24 g, 0.59 mmol) was added 2-(methyamino)ethanol (2.0 mL) and the solution was heated at 80° C. for 18 h. A saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to give a residue which was purified by chromatography (silica, 30% ethyl acetate in hexane) to give an oil (0.16 g, 68%): 1H NMR (CDCl3) δ 8.50 (1H, brs), 8.01 (1H, s), 7.30 (6H, m), 6.77 (1H, d, J=8.4 Hz), 5.02 (2H, m), 4.59 (2H, m), 4.77 (1H, brs), 4.09 (1H, m), 3.69 (1H, m), 3.36 (2H, m), 2.93 (3H, s), 1.26 (3H, d, J=6.4 Hz); MS (ES) m/z 399 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1/[CH:8]=[N:9]/[S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11].[CH3:16][Mg]Br.[Cl-].[NH4+]>ClCCl>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C@@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH3:16]
Reactant: C[Mg]Br
Reactant: Cn1ncc(/C=N/[S@](=O)C(C)(C)C)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cnn(C)c1Cl
Temperature: -78 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
(R,E)-N-((5-chloro-1-methyl-1H-pyrazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (100 mg, 0.404 mmol) was dissolved in dichloromethane (10 ml) placed under nitrogen and cooled to −78° C. 1.4M methyl magnesium bromide solution (toluene:THF 3:1, 1.04 ml, 1.45 mmol) was added dropwise and reaction stirred overnight while warming to room temperature. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction and stirred for 5 minutes. The product was extracted with EtOAc (2×15 ml), combined organics were washed with brine (15 ml), dried over Na2SO4, filtered and concentrated and purified by silica gel column chromatography eluted with heptane/ethyl acetate=100/0 to 0/100 to furnish the title product as a clear gum (57 mg, 53% yield). 1H NMR (400 MHz, CD3OD) 1.18-1.19 (9H s) 1.54-1.56 (3H d) 3.81-3.82 (3H s) 4.41-4.47 (1H q) 7.50-7.51 (1H s) MS (ESI) m/z 264 (M+H)+