Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Zn](CC)[CH2:2]C.FC(F)(F)C(O)=O.N#N.C(I)I.[CH3:18][C:19]1([CH3:34])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[CH2:33])[CH:27]=2)[O:20]1>C(Cl)Cl>[CH:32]1([C:28]2[CH:27]=[C:26]([B:21]3[O:20][C:19]([CH3:34])([CH3:18])[C:23]([CH3:24])([CH3:25])[O:22]3)[CH:31]=[CH:30][CH:29]=2)[CH2:2][CH2:33]1
Reactant: CC[Zn]CC
Reactant: C=Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Solvent: ClCCl
Product: CC1(C)OB(c2cccc(C3CC3)c2)OC1(C)C
Reaction time: 0.33 h
Yield: 10 %

Procedure:
To a solution of Zn(C2H5)2 (1 M, 6 mL) in DCM (1 mL) was added trifluoro-acetic acid (0.46 ml, 6 mmol) in DCM (1 mL) very slowly under N2 in ice bath. The mixture was stirred for 20 minutes. CH2I2 (1.61 g, 6 mmol) in DCM (1 mL) was added to the mixture. After stirring for 20 minutes, 4,4,5,5-tetramethyl-2-(3-vinylphenyl)-1,3,2-dioxaborolane (690 mg, 3 mmol) in DCM (1 mL) was added. The mixture was stirred at room temperature for 2 hour. the mixture was quenched by NH4Cl solution, extracted with DCM 3 times, washed with brine, filtered and concentrated to give the residue, which was purified preparative TLC and HPLC to give 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[Si:34]([O:19][CH2:18][CH2:17][N:13]1[C:14]([CH2:15][CH3:16])=[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1nn(CCO)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CCO[Si](C)(C)C(C)(C)C)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.4 %

Procedure:
To a solution of Example 46 (1.03 g, 2.65 mmol) in dimethylformamide (5 ml) was added imidazole (361 mg, 5.30 mmol), followed by tert-butyldimethylchlorosilane (600 mg, 3.97 mmol). The solution was stirred at room temperature for 4 days. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane:ethyl acetate (20:1, by volume), followed by cyclohexane:ethyl actetate (5:1, by volume) to afford the title compound (1.1 g) as a white powder, m.p. 83-84° C.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]([N:12]([C:30](=[O:33])[CH2:31][CH3:32])[C:13]1[C:18]([S:19](O)(=[O:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH2:10][CH3:11].P(Cl)(Cl)(Cl)(Cl)[Cl:35].CCOCC>ClCCl>[O:8]=[C:9]([N:12]([C:30](=[O:33])[CH2:31][CH3:32])[C:13]1[C:18]([S:19]([Cl:35])(=[O:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH2:10][CH3:11]
Reactant: CCC(=O)N(C(=O)CC)c1c(-c2cccc(C)c2)cccc1S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(C(=O)CC)c1c(-c2cccc(C)c2)cccc1S(=O)(=O)Cl

Procedure:
To a solution of 3.6 g (7.6 mmol) of the N,N-diethylethanamine salt of 2-[bis(1-oxopropyl)amino]-3'-methyl[1,1'-biphenyl]-3-sulphonic acid in 8 ml of dichloromethane, at 0° C., are added 1.6 g (7.6 mmol) of phosphorus pentachloride and the mixture is allowed to return to room temperature. The mixture is then heated for 4 hours at the reflux temperature and is then allowed to return to room temperature. Ether is added, the mixture is filtered, the filtrate is concentrated and the residue is purified on a column of florisil™, eluting with an ether/pentane mixture (1/1). The product is recrystallized from an ether/pentane mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH:27]1(B(O)O)[CH2:29][CH2:28]1>O1CCOCC1.Cl[Pd-2](Cl)([P+](C1C=CCC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CCC=1>[CH:27]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=2[N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH2:29][CH2:28]1
Reactant: OB(O)C1CC1
Reactant: CN1CCN(c2c(Br)cncc2[N+](=O)[O-])CC1
Agent: Cl[Pd-2](Cl)([P+](C1=CCC=C1)(c1ccccc1)c1ccccc1)[P+](C1=CCC=C1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCN(c2c(C3CC3)cncc2[N+](=O)[O-])CC1
Temperature: 100 °C

Procedure:
A mixture of 1-(3-bromo-5-nitro-4-pyridyl)-4-methyl-piperazine (synthesized from 1-methylpiperazine and 3-bromo-4-chloro-5-nitropyridine using procedure Step 1 of Preparation N-1) (467.4 mg, 1.552 mmol), ferrous; dichloro-bis[cyclopenta-1,4-dien-1-yl(diphenyl)phosphaniumyl]palladium(2-); dichloromethane (63.37 mg, 0.07760 mmol), potassium carbonate (429.0 mg, 3.104 mmol) and cyclopropylboronic acid (200.0 mg, 2.328 mmol) in dioxane (5 mL) was degassed and flushed with nitrogen (×2). The reaction was heated at 100° C. in a sealed tube for 18 h. At room temperature the reaction mixture was filtered through Celite and evaporated to dryness, yielding 1-(3-cyclopropyl-5-nitropyridin-4-yl)-4-methylpiperazine as a dark orange solid that was used directly in the next reaction without further purification (288 mg, 66%). MS (ES+) 263.2
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].IC.[OH-].[K+].[CH3:20]S(C)=O>O>[CH3:20][N:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11]1=[O:15]
Reactant: O=C1NCCN1c1ccc([N+](=O)[O-])cc1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 21 parts of 1-(4-nitrophenyl)-2-imidazolidinone, 16 parts of iodomethane, 10 parts of potassium hydroxide and 200 parts of dimethyl sulfoxide was stirred for 3 hours at room temperature. Another portion of 16 parts of iodomethane and 10 parts of potassium hydroxide were added. Stirring was continued overnight. 300 Parts of water were added to the reaction mixture and the whole was stirred. The precipitated product was filtered off and crystallized from 4-methyl-2-pentanone, yielding 16.5 parts (74%) of 1-methyl-3-(4-nitrophenyl)-2-imidazolidinone; mp. 214.1°-215.5° C. (7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[O:28][N:27]=1)([CH3:25])[CH3:24].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[O:28][N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Temperature: 25 °C
Yield: 19 %

Procedure:
A stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.30 mmol), phenyl 3-isopropylisoxazol-5-ylcarbamate from the previous step (89 mg, 0.36 mmol), N,N-diisopropylethylamine (58 mg, 0.45 mmol) and 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) in dry tetrahydrofuran (1.5 mL), was heated at 50° C. for 30 mins. After cooling to room temperature, concentration under reduced pressure gave a residue which was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (using phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea as a colorless solid (25 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ 10.30 (brs, 1H), 9.14 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.39-7.44 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 5.99 (s, 1H), 4.00 (s, 6H), 2.90 (septet, J=6 Hz, 1H), 1.19 (d, J=6 Hz, 6H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[C:17](Cl)([Cl:19])=[O:18].[CH:21]([OH:24])([CH3:23])[CH3:22].C(OCC)C>C(#N)C.C1(C)C=CC=CC=1>[ClH:19].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:17]([O:24][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Reactant: CC(C)O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)OC(C)C)ccc1NC1=NCCC1

Procedure:
To 1.2 g (4.6 mmole) of the product compound of Example 9 in 30 ml of acetonitrile was added a 10% excess of phosgene in toluene. The mixture was stirred at 20° in the absence of moisture for 16 hours, at which time a large excess (20 ml) of isopropyl alcohol was added. The reaction mixture was stirred at 20° until reaction was complete, as indicated by thin-layer chromatography on silica gel (9:1 ethanol/concentrated aqueous ammonia or 74:25:1 dichloromethane/ethanol/ammonia). The product was taken up in an eight-fold excess of diethyl ether and recovered as an oil by concentrating the extract. The title compound crystallized upon standing. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10]1.CC(C)([O-])C.[K+].Cl[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37].Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][C:28]=3[N+:36]([O-:38])=[O:37])[CH:15]=2)[O:10]1
Reactant: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc2c(c1)CCC(c1cc(F)ccc1F)O2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ccc3c(c2)CCC(c2cc(F)ccc2F)O3)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
320 mg of 2-(2,5-Difluorophenyl)chroman-6-ol (Example 14(c)) was dissolved in dry DMF and potassium tert-butoxide (150 mg) was added. The resulting mixture was stirred for 30 minutes and 1-chloro-4-ethoxy-2-nitrobenzene (250 mg) was added. The reaction mixture was refluxed for 8 hours. After cooling to room temperature 1 M HCl-solution was added into the reaction mixture and it was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated NaCl-solution. The product was purified by column chromatography using heptane-ethyl acetate (3:1) as an eluant. 1H NMR (300 MHz, CDCl3) δ: 7.43 (d, 1H, J 2.9Hz), 7.25 (m, 1H), 7.08-6.97 (m, 4H), 6.89-6.75 (m, 3H), 5.31 (d, 1H, J 9.1 Hz), 4.06 (q, 2H, J 7.0 Hz), 2.97 (m, 1H), 2.74 (m, 1H), 2.26 (m, 1H), 1.98 (m, 1H), 1.44 (t, 3H, 7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[S:21][C:22]1[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:27]([C:25]3[O:26][C:22]([S:21][C:13]4[NH:12][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=5[N:14]=4)=[CH:23][CH:24]=3)[C:30]3[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:29]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(Sc2nc3ccccc3[nH]2)o1
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Alternatively example 105 can be prepared by reacting 3-amino-2-ethoxycarbonyl-pyrrole (31.5 g, 204 mmol), 5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (50 g, 204 mmol) and 1,3-cyclohexanedione (22.95 g 204 mmol) in 2.5 l of 1-butanol at reflux temperature for 3 hours. The reaction mixture is then concentrated under reduced pressure. The residue is resuspended in 1 l of ethanol and heated to reflux temperature for 2 hours and let to cool to room temperature. The formed insoluble material is collected by filtration, washed with ethanol (0.4 l), diisopropyl ether (0.4 l), pentane (0.4 l) and dried under vacuum. The residue is resuspended in 2 l of acetonitrile, heated to reflux temperature for 2 hours and let to cool to room temperature. The insoluble material is collected by filtration, washed with acetonitrile (0.6 l), diisopropyl ether (0.6 l), pentane (0.6 l) and dried under vacuum to yield 41.5 g of 9-[5-(1H-Benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester in the base form as a light gray powder. Yield=43%. Analytical LC/MS method B: retention time=3.32 min. m/z=475.06 (positive ion mode).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH3:28][NH:29][CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1)[OH:32].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:29]([CH2:30][CH:31]([OH:32])[C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[CH:37][CH:38]=4)[CH3:28])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccc(N2CCOCC2)cc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc(N3CCOCC3)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-(4-morpholin-4-ylphenyl)ethanol dihydrochloride (Preparation 89) (118 mg, 0.38 mmol) and diisopropylethylamine (180 μL, 1.0 mmol) in dry DMF (5.0 mL) was stirred for 48 hours at room temperature. The solution was diluted with water (10 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (76 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45]CC2C=CC=CC=2)=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H][H].C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:53])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCO)cc1
Reaction time: 4 h

Procedure:
In a nitrogen atmosphere, to a suspension of palladium hydroxide (20% by weight; 145 mg) in methanol (4 ml), a solution of Compound 25 (655 mg, 0.868 mmol) in methanol (6 ml) was added; after the nitrogen atmosphere was replaced with a hydrogen atmosphere, stirring was conducted at room temperature for 4 hours. After a nitrogen atmosphere was restored, ethyl acetate (about 10 ml) was added, and this was followed by filtration on silica gel and washing with an ethyl acetate solution containing 10% methanol. Concentration under reduced pressure was conducted to yield a crude product of Compound 26.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10].C1COCC1.CCOC(C)=O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][CH3:9])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CNc1cc(Cl)ncn1
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (7.45 g, 50 mmol) in iPrOH (50 mL) was added a solution of methyl amine in THF (2M, 30 mL, 60 mmol) at room temperature. The resulting mixture was stirred for 18 hours. The mixture was concentrated and the residue was purified by flash chromatography on silica eluting with DCM:EtOAc=6:1-1:1 to obtain the title compound (4.4 g, yield: 62%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.96 (d, 3H), 5.22-5.36 (bs, 1H), 6.35 (s, 1H), 8.35 (s, 11H); MS (ESI): 144 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=4)[CH2:17][CH2:16][N:15]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CCCCCC.CN(C)C=O>[C:31]([O:30][C:29](=[O:35])[NH:28][CH2:27][CH2:26][O:24][C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][N:15]=[C:14]2[C:10]2([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:19][CH:20]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2

Procedure:
Sodium hydride (0.626 g, 15.64 mmol, 60% suspension in mineral oil) was washed under dry conditions under nitrogen atmosphere with n-hexane. Dimethylformamide (20 mL) was added followed by 1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (2.1 g, 7.11 mmol) under stirring. After the exothermic reaction had ceased stirring was continued at room temperature for 1 h before tert-butyl (2-bromoethyl)carbamate (4.78 g, 21.33 mmol) was added dropwise as a solution in dimethylformamide (10 mL). The reaction mixture was stirred at room temperature over night. The solvent was evaporated in vacuo. Ice water was added (60 mL) and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane:methanol=100:1). Yield: 2.5 g (5.7 mmol, 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13]C)=[O:11])=[CH:7][C:6]=2[CH:15]=1.C(B(CC)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>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>[CH3:13][O:12][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:6]=2[CH:7]=1)=[O:11]
Reactant: CCB(CC)c1cccnc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(-c3cccnc3)ccc2o1
Temperature: 100 °C
Yield: 184.2 %

Procedure:
A mixture of ethyl 5-bromo-benzofuran-2-carboxylate 15 (6 g, 22.3 mmole), diethyl 3-pyridylborane (3.66 g, 25 mmole), tetrakis(triphenylphosphine)palladium (0) (270 mg), and potassium phosphate (11.4 g, 53.7 mmole) in DMF (60 ml) was stirred under an argon atmosphere and heated to 100° C. for 16 hrs. The mixture was allowed to cool to room temperature, poured into ethyl acetate and washed with 10% HCl. The organic layer was washed with brine, dried, and evaporated to give 10.4 g of 5-pyridin-3-yl-benzofuran-2-carboxylic acid methyl ester. 534 mg the carboxylic ester were then dissolved in 11 ml t-butanol and stirred under nitrogen. Addition of 198 mg NaBH4 followed by 1.75 ml methanol and the reaction was stirred at 55° C. overnight. After cooling, the reaction was poured into brine and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by chromatography to give 330 mg of (5-pyridin-3-yl-benzofuran-2-yl)-methanol 61.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:34]=[CH:33][C:17]([C:18]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[NH:7][CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:47].Cl>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[O:19])=[CH:33][CH:34]=3)=[CH:11][CH:12]=2)[N:7]([C:46]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:47])[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2NC[C@@H]1C
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCNCC4)cc3)cc2N(C(=O)Oc2ccccc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A reaction vial was charged with (S)-tert-butyl 4-(4-(1-acetyl-2-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)benzoyl)piperazine-1-carboxylate (0.2 M in 1,2-dichloroethane, 100 μL, 0.02 mmol), N,N-diisopropylethyl amine (25 μL, 0.14 mmol), and phenyl chloroformate (6.23 mg, 0.04 mmol), and the mixture was shaken at 50° C. for 2 h. Methanol (50 μL) was added and the mixture was shaken at 50° C. for 10 min. HCl (4 M in dioxane, 0.075 mL, 0.30 mmol) was added and the reaction was shaken at 50° C. for 2 h. The mixture was concentrated and the residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford phenyl (S)-4-acetyl-3-methyl-7-(4-(piperazine-1-carbonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 499.