Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]=[O:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1
Reactant: Brc1ccccn1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(O)c3ccccn3)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a solution of 2-bromopyridine (0.10 mL, 1.04 mmol) in THF (3 mL) at −78° C. is added n-BuLi (0.39 mL, 0.98 mmol, 2.5 M solution in hexane). After stirring for 10 minutes at −78° C., a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehyde 10 h (25 mg, 0.064 mmol) in THF (1 mL) is added. The resulting reaction mixture is stirred for 1.5 hours at −78° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (2.5% MeOH in CH2Cl2) to afford the desired product (18 mg, 62%): MS APCI (+) m/z 461, 463 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.31 (d, 1H), 8.16 (s, 1H), 7.65 (m, 3H), 7.38 (d, 1H), 7.10 (m, 1H), 7.00 (dd, 1H), 6.11 (dd, 1H), 6.05 (s, 1H), 3.94 (s, 3H); 19F NMR (376 MHz, CD3OD) −135.79 (s).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10](=[O:26])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[CH2:4][O:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccncc2Nc2ccc(I)cc2F)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOC[C@H](O)CO)c1ccncc1Nc1ccc(I)cc1F
Temperature: 25 °C

Procedure:
A suspension of N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (synthesis described below) (3.0 g, 6.16 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (20 mL) and the clear-yellow solution was stirred at room temp. After stirring for 8 h, the contents were concentrated to a yellow oil, which was dissolved in ethyl acetate (100 mL) and poured into water (150 mL). The pH of the biphasic mixture was adjusted between 6 and 7 with 2.0 N aqueous sodium hydroxide and the layers were separated. The organics were dried over sodium sulfate, concentrated to a yellow oil and placed under high vacuum at 40° C. The resultant yellow, solid foam weighed 2.39 g (5.34 mmol, 87%) after drying for 18 h. LC/MS [5.22 min; 448 (M+1)]
Reaction SMILES: [ClH:1].[O:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)=[CH:9][CH:8]=2)=[N:3]1>C(OCC)(=O)C.CO>[ClH:1].[ClH:1].[O:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:18][NH:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(-c3ncon3)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: c1nc(-c2ccc([C@H]3CNCCN3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Hydroxylamine hydrochloride (1.3 g, 20.2 mmol) and sodium carbonate (3.4 g, 32.1 mmol) were added to a solution of di-tert-butyl (2S)-2-(4-cyanophenyl)piperazine-1,4-dicarboxylate (2.5 g, 6.45 mmol) in ethanol (15 ml) and water (15 ml) at the room temperature and the solution was stirred at 80° C. for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Triethyl orthoformate (9.6 g, 64.8 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) were added to a solution of the residue in toluene (25 ml) and stirred at 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish di-tert-butyl (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)-piperazine-1,4-dicarboxylate (1.94 g, 70%) as a colorless oil. Hydrogen chloride in ethyl acetate (4N) was added to a solution of di-tert-butyl (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylate (1.94 g, 4.51 mmol) in methanol and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure to give white solid, which was washed with ethyl acetate to afford (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)piperazine dihydrochloride (1.3 g, 95%) as white crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([S:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]1=2)(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([S:16]([CH2:17][CH2:18][CH2:19][CH3:20])=[O:33])=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]1=2)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCSc1ccc2c(c1)C=Cc1ccccc1N(C(C)=O)C2
Solvent: ClCCl
Product: CCCCS(=O)c1ccc2c(c1)C=Cc1ccccc1N(C(C)=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 135.8 %

Procedure:
To a solution of compound Example 287A (32 mg, 0.095 mmol) in CH2Cl2 (5 mL) at 0° C. was added mCPBA (13 mg, 0.05 mmol). The solution was stirred for 1 hour at 0° C. and for 1 hour at room temperature. The reaction was quenched by adding NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×2 mL). The combined EtOAc extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 2:1 hexane/EtOAc) to give the title compound (24 mg, 77 %). HPLC Rt=3.7 min. m/z=354(M+H+).
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[C:12]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:7])C.Cl>O.O1CCOCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]2[O:10][C:9]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[C:8]([C:5]([OH:1])=[O:7])[C:12]=2[CH:13]=1)#[N:18]
Reactant: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(C)=O)cc1
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(=O)O)cc1
Yield: 34.6 %

Procedure:
5.2 g of sodium hydroxide was dissolved in 30 ml of water, and the solution was cooled to a temperature of 0° C. or below. With stirring, to this were added dropwise 2.7 ml of bromine and then 40 ml of a dioxane solution containing 4.14 g of 3-acetyl-2-[2-(4-methoxyphenyl)ethyl]-5-benzofurancarbonitrile obtained in the above step d). The resulting mixture was stirred at 0° C. for 45 minutes with ice cooling for 1 hour. The resulting reaction solution was mixed with water, adjusted to pH 2 with concentrated hydrochloric acid, and then extracted with chloroform. The resulting organic layer was washed with water and dried to distill off the solvent. Thereafter, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an eluant, thereby obtaining 1.44 g of 5-cyano-2-[2-(4-methoxyphenyl)ethyl]-3-benzofurancarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[O:17]=[C:18]1[N:23]([CH2:24][CH2:25][CH2:26][CH:27]=O)[CH2:22][CH2:21][CH2:20][O:19]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:27][CH2:26][CH2:25][CH2:24][N:23]3[CH2:22][CH2:21][CH2:20][O:19][C:18]3=[O:17])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=CCCCN1CCCOC1=O
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCN(CCCCN1CCCOC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (ca.13 mg 50 umole), was added 440 μL solution of 4-(2-oxo-[1,3]oxazinan-3-yl)-butyraldehyde (0.125 M in 1,2 dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 M slurry of sodium triacetoxyborohydride in 1,2 dichloroethane. The reaction was shaken at room temperature for 48 h. After quenching with 2 mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL water and ethyl acetate to workup flasks. The organic phase was washed, dried and concentrated. Purification by chromatography yielded 3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one 19, MS: 375 ([M+H]+).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8].CO>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8]
Reactant: COC(=O)c1sc2cc(OC)ccc2c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1sc2cc(O)ccc2c1C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Boron tribromide (5.0 ml.) was added dropwise to a stirred solution of 6-methoxy-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (4.70 g.) in dry methylene chloride (200 ml.) at -78° C. and the resulting suspension was stirred at -78° for 15 minutes followed by 24 hours at room temperature. The mixture was then treated cautiously with methanol and the solution was washed with sodium bicarbonate solution. The organic layer was dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform first gave a trace of impurity followed by pure product. The product-containing fractions were evaporated to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 6-hydroxy-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (3.58 g.), m.p. 174°-176°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[C:4]([CH3:18])[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[F-].[Cs+]>COCCOC.O>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(C#N)Cc1cccnc1
Reactant: COCCCc1ccccc1B(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cccnc2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution 2-(4-bromo-2-methylphenyl)-3-pyridin-3-ylpropanenitrile (1 eq.) from step 1 and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 (1.2 eq.) in DME (0.1M) at room temperature was added palladium tetrakistriphenyl phosphine (Pd(PPh3)4; 0.05 eq.) and CsF (2.4 eq.). The mixture was refluxed for 2 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with water, brine, dried over Na2SO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 65% in 30 min) afforded the desired compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH:17]=O.N1CCCCC1>C(O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1/[CH:17]=[C:6]1/[C:2](=[O:1])[N:3]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:4](=[S:7])[S:5]/1
Reactant: O=C(O)CCN1C(=O)CSC1=S
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(OC)c(/C=C2\SC(=S)N(CCC(=O)O)C2=O)c1
Yield: 87.4 %

Procedure:
3-(4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (200 mg, 1 mmol), 2,5-dimethoxy benzaldehyde (168 mg, 1 mmol) and piperidine (0.3 mL) were combined in ethanol (3 mL) and irradiated in the microwave at 100° C. for 10 minutes. The reaction was cooled, the solid was collected by filtration, washed with ethyl acetate/hexanes (1/1) and recrystallized from ethanol to afford 85% yield of the title compound (309 mg, brown-orange solid). MS (M+H, 284); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.57 (t, 2H)), 3.74 (s, J=6.8 Hz, 3H), 3.84 (s, 3H), 4.19 (t, 2H), 6.90 (s, 1H), 7.10 (s, 2H), 7.86 (s, 1H).
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][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.[C:33](OC(=O)C)(=[O:35])[CH3:34].C1COCC1>O>[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:33](=[O:35])[CH3:34])[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(=O)OC(C)=O
Reactant: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Reaction time: 3 h
Yield: 54.5 %

Procedure:
3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio) pyridin-2-amine (0.075 g, 0.16 mmol), TEA (0.090 mL, 0.65 mmol), and acetic anhydride (0.017 g, 0.16 mmol) were added to THF and stirred for 3 hr. Water was added and extracted with CH2Cl2. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel (5% MeOH in CH2Cl2) to provide the title compound (0.044 g, 54% yield). 1H NMR (d6-DMSO) δ 12.34 (s, 1H), 8.38 (m, 2H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.32 (d, 1H), 3.84 (d, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.76 (t, 1H), 2.01 (m, 5H), 1.74 (m, 1H), 1.59 (m, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[CH2:15][O:16][CH3:17])=[CH:11][C:10]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:9][CH:8]=3.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]1[CH:4]=[N:3][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([CH2:15][O:16][CH3:17])[C:13]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCc1c(Br)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCc1c(-c2ccccc2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
476 mg of 3-bromo-6-benzyloxy-4-methoxymethyl-β-carboline is introduced in 10 ml of toluene and 5 ml of ethanol, mixed with 41 mg of tetrakis(triphenylphosphine)-palladium(0) and stirred for 5 minutes. Then 177 mg of phenylboronic acid and 1.5 ml of a 2 m- soda solution are added and then heated for 3 hours to 95° C. After concentration by evaporation it is taken up in a lot of ethyl acetate and washed once each with water and saturated common salt solution. After drying, filtration and concentration by evaporation, it is recrystallized. 372 mg of 6-benzyloxy-3-phenyl-4-methoxymethyl-β-carboline of a melting point of 205°-206° C. (ethanol, methylene chloride, hexane) is obtained.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C1COCC1>[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH:26][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(CN)OC
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCC(OC)OC
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a stirred solution of methyl 2-chloro-3-nitrobenzoate (1.1 g, 4.9 mmol) from Step A above in THF (33 mL) was added triethylamine (0.8 mL, 6.0 mmol) followed by 2,2-dimethoxyethanamine (0.7 mL, 6.0 mmol) at room temperature. The reaction mixture was stirred overnight at reflux. The suspension was concentrated under reduced pressure and purified by column chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) to afford methyl 2-(2,2-dimethoxyethylamino)-3-nitrobenzoate (1.4 g, 98%): 1H NMR (500 MHz, DMSO-d6) δ 8.39 (t, J=4.5 Hz, 8.08-8.05 (m, 2H), 6.83 (t, J=8.0 Hz, 1H), 4.54 (t, J=5.0 Hz, 1H), 3.87 (s, 3H), 3.31 (s, 6H), 2.93 (t, J=5.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].C(N(CC)CC)C.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[S:25](Cl)(=[O:27])=[O:26]>CC(C)=O>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[S:25]([O:9][C:4]1[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([NH2:1])[CH:3]=1)(=[O:27])=[O:26]
Reactant: Nc1ccc(O)cc1N
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Nc1ccc(OS(=O)(=O)c2c(F)cccc2F)cc1N
Temperature: 20 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To a solution of 2 g of 3,4-diaminophenol in 150 cm3 of acetone are added 2.264 cm3 of triethylamine and 3.425 g of 2,6-difluorobenzenesulfonyl chloride. The reaction medium is stirred at a temperature in the region of 20° C. overnight. The insoluble material is filtered off and rinsed with three times 50 cm3 of acetone, and the filtrate is evaporated to dryness under reduced pressure (3.5 kPa). The residue is taken up in 300 cm3 of dichloromethane, washed with three times 50 cm3 of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)], 650 mg of 3,4-diaminophenyl 2,6-difluorobenzenesulfonate are obtained in the form of a black resin, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(#N)C>[CH2:19]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nccc2cc(OC3CCCNC3)ccc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1nccc2cc(OC3CCCN(Cc4ccccc4)C3)ccc12
Reaction time: 0.33 h
Yield: 102.3 %

Procedure:
A couple of drops of glacial acetic acid was added to a solution of racemic 6-(piperidin-3-yloxy)-isoquinolin-1-ylamine (52 mg, 0.214 mmol) and benzaldehyde (26 mL, 0.256 mmol) in acetonitrile (2 ml). The mixture was stirred for 20 minutes and then sodium triacetoxyborohydride (68 mg, 0.321 mmol) was added in portions. The mixture was stirred at ambient temperature for 20 h then concentrated in vacuo. The mixture was then partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate. The organic layer was separated then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give 6-(1-benzylpiperidine-3-yloxy)isoquinolin-1-yl amine (73 mg) El-MS: m/z=334.3 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:7][CH:6]=1>C1COCC1.CSC>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([CH3:1])[CH2:12][C:13]([N:15]2[C@H:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:9][CH:10]=1
Reactant: O=C(/C=C/c1ccc(Br)cc1)N1C(=O)OC[C@H]1c1ccccc1
Reactant: C[Mg]Br
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@H](CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
To a stirred solution of copper(II) bromide dimethylsulfide complex (8.78 g, 42.7 mmol) in THF (60 mL) and dimethylsulfide (30 mL) was added methylmagnesium bromide (12.7 mL, 3.0M in diethyl ether, 38.1 mmol) at −40° C. The resultant mixture was stirred at −40° C. for 30 min, then warmed to −20° C. The product from Step A (3.53 g, 9.48 mmol) in THF (30 mL) was added to the above reaction mixture over 1 h at −20° C. The resultant mixture was stirred at −20° C. for 2 h, then slowly warmed to room temperature and stirred at room temperature for 12 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 83:17 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24](I)=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[S:42]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43]1>CN(C=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>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9](=[O:10])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([C:44]4[CH:45]=[CH:46][S:42][CH:43]=4)=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
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: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(-c4ccsc4)sc23)CC1
Temperature: 90 °C
Yield: 34.2 %

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.080 mmol) in DMF (3 mL) were added 2M Na2CO3 (0.1 mL) and 3-thiophenyl boronic acid (15 mg, 0.117 mmol). The mixture was bubbled N2 for 20 minutes and then Pd(PPh3)4 (10 mg, 0.012 mmol) was added. The mixture was heated to 90° C. for 12 hours. The solvent was removed under vacuum and the residue was subject to chromatography on silica gel to afford the product {1-(4-chlorobenzyl)-2-oxo-2-[4-(6-thiophen-3-yl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (16 mg, 34.4%). 1H NMR (CDCl3, 400 Hz) δ 8.57 (s, 1H), 7.70-7.42 (m, 4H), 7.27 (d, J=8.4, 2H), 7.16 (d, J=8.4 Hz, 2H), 5.36 (d, J=8.8 Hz, 1H), 4.87-4.84 (m, 1H), 3.91-3.59 (m, 7H), 3.27-3.24 (d, J=11.2 Hz, 1H), 3.00-2.99 (d, J=7.2 Hz, 2H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 584.