Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([OH:15])[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1.I[CH2:23][CH2:24][CH3:25]>CCOCC>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:23][CH2:24][CH3:25])[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1
Reactant: Cn1nc(-c2ccccc2)c(O)c1-c1ccccc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (57%, 0.92 g, 0.022 mole) is added slowly to a suspension of 1-methyl-3,5-diphenyl-4-pyrazolol (5 g, 0.02 mole) in anhydrous ether (100 ml). An off-white precipitate forms. After stirring for 45 minutes, the solid is removed by filtration, added to dry DMF (30 ml) and treated with 1-iodopropane (5 ml, 0.05 mole). The reaction mixture is stirred, heated at 60° C for 14 hours and then poured into ice water (600 ml). After standing for 24 hours in the refrigerator, a tacky yellow solid is formed. Recrystallization from hexane at -20° C affords an off-white solid, melting point 56°-57° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)(=[O:30])=[O:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)=[C:14]([O:38][CH3:39])[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:39][O:38][C:14]1[CH:13]=[C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:17]=[CH:16][C:15]=1[C:18]1[C:27]2[C:22](=[CH:23][C:24]([S:28]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: Cc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccccc2C)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 150 °C
Yield: 32.4 %

Procedure:
A microwave vial charged with 2-methylphenylboronic acid (0.022 g, 0.158 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1′1′-biphenyl (4.33 mg, 10.54 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (7.99 mg, 10.54 μmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 160; 45 mg, 0.105 mmol), potassium phosphate (90 mg, 0.422 mmol), 1 mL dioxane and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product, so the aqueous layer was removed. The reaction mixture was acidified with 4N HCl in dioxane then was concentrated. The crude product was purified by reverse phase column chromatography [PREP LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min 10-40%_LV_NH3] yielding 1-(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.017 g, 0.034 mmol, 32.6% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 3.68 (s, 3H) 6.95 (br. s., 1H) 7.08 (d, J=7.27 Hz, 1H) 7.14 (s, 1H) 7.27 (br. s., 1H) 7.29-7.44 (m, 5H) 7.78 (d, J=8.82 Hz, 1H) 7.97 (d, J=8.71 Hz, 1H) 8.08 (d, J=5.96 Hz, 1H) 8.18 (br. s., 1H) 8.52 (br. s., 1H) 8.62 (br. s., 1H) 8.68 (d, J=5.56 Hz, 1H); (M+H)+=483.0.
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:14][CH2:11]/[CH:10]=[CH:9]/[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC/C=C/C#Cc1ccccc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: BrC/C=C/C#Cc1ccccc1
Yield: 65.7 %

Procedure:
A solution of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method 1b) (980 mg, 6.2 mmol) in dry toluene (20 mL) was cooled on ice and phosphorus tribromide (0.59 mL, 6.2 mmol) added slowly. After 16 h at 5° C. the mixture was diluted with ethyl acetate and washed with water (×3). The organic phase was concentrated in vacuo and the residue extracted with heptane (×3). The combined heptane phases were concentrated in vacuo to give 900 mg of crude (E)-(5-bromo-pent-3-en-1-ynyl)-benzene. (According to NMR the product contained ˜5% of the (Z)-isomer).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:13]=[O:14]>[OH-].[Na+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([CH2:13][OH:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(Br)ccc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2cc(Br)ccc2c1O

Procedure:
7-Bromo-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 7-bromo-4-hydroxy-3-hydroxymethylquinoline, m.p. >300°
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[N:12]=[C:11]([F:16])[CH:10]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([C:23](=O)[CH3:24])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[N:12]=[C:11]([F:16])[CH:10]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH:23]([NH2:32])[CH3:24])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2cc(F)nc(F)c2)c1-c1ccccc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2ccccc2)c1-c1cc(F)nc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanone (60 mg, 0.2 mmol), ammonium acetate (130 mg, 1.7 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (60 mg, 100%). LCMS calculated for C20H15ClF2N (M−NH2)+: m/z=342.1. found: 342.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([OH:24])(=[O:23])[C:17]([CH2:19][C:20](O)=[O:21])=[CH2:18]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:13]2[C:20](=[O:21])[CH2:19][CH:17]([C:16]([OH:24])=[O:23])[CH2:18]2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
18.8 g (94.4 mmol) 4-benzyloxyaniline are mixed with 12.28 g (94.4 mmol) itaconic acid. The mixture is heated to 130° C. After 20 min the melted material solidifies. The resulting solid is triturated with ethyl acetate to yield 28.26 g (96%) of a greyish solid. MS: m/e=311 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[CH3:11][NH:12][C:13]([C:15]1[C:19]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:18]=2[O:17][C:16]=1[CH3:25])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:11][NH:12][C:13]([C:15]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)=[CH:23][C:18]=2[O:17][C:16]=1[CH3:25])=[O:14]
Reactant: Clc1ccnc2ccsc12
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4ccsc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine with 6-hydroxy-2-methylbenzofuran-3-carboxylic acid methyl amide 12c and Cs2CO3 in a manner as previously described for example 1. 1H NMR (CD3CN) δ 8.48 (1H,d, J=5.3 Hz), 7.91 (1H, d, J=5.6 Hz), 7.84 (1H, d, J=8.6 Hz), 7.53 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=2.0 Hz), 7.20 (1H, dd, J=8.6, 2.0 Hz), 6.62 (1H, d, J=5.3 Hz), 6.60 (1H, bm), 2.91 (3H, d, J=4.6 Hz) 2.66 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([CH3:18])[N:15]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:14]=1)(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(C)=O>[C:31]([N:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])[S:10]([C:13]1[N:17]=[C:16]([CH3:18])[N:15]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:14]=1)(=[O:11])=[O:12])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1nc(S(=O)(=O)Nc2c(F)cccc2F)nn1-c1ncccn1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nc(S(=O)(=O)N(C(=O)c2ccccc2)c2c(F)cccc2F)nn1-c1ncccn1
Reaction time: 18 h
Yield: 54 %

Procedure:
A suspension of N-(2,6-difluorophenyl)-5-methyl-1-(2-pyrimidinyl)-1,2,4-triazole-3-sulphonamide (1.5 g) (Compound A54) and anhydrous potassium carbonate (0.59 g) in dry acetone (50 ml) was heated under reflux for 30 minutes. A solution of benzoyl chloride (0.6 g) in acetone (50 ml) was added, and the mixture was refluxed for a further 2 hours. The mixture was then allowed to stand at 25° C. for 18 hours, after which it was warmed, filtered and evaporated. The solid produced was recrystallised from acetonitrile to give 1.05 g of the desired product, mp 218°-221° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11](=[O:12])[CH:10]=[CH:9][O:8][C:7]=1[CH3:13].[OH-].[K+].[CH3:16]I>>[CH3:16][O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11](=[O:12])[CH:10]=[CH:9][O:8][C:7]=1[CH3:13]
Reactant: CI
Reactant: Cc1occc(=O)c1OCCCO
Agent: [K+]
Agent: [OH-]
Product: COCCCOc1c(C)occc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
A mixture of 3-(3-hydroxy-1-propoxy)-2-methyl-4-pyrone {1.4 g, 7.6 mmol), 85% KOH (0.55 g, 8.4 mmol) and methyliodide (11 g, 76 mmol) was stirred at room temperature for one day. The red solution was partitioned between methylene chloride and half saturated aqueous ammoniumchloride solution. The organic phase was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on silica gel with methanol/methylene chloride (3:97) as eluent. Removing the eluent by film evaporation afforded 0.31 g (20%) of the desired product as an oil.
Reaction SMILES: CO[C:3](=[O:25])[CH:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:16][C:14]([F:15])([F:17])[C:12]1[N:13]=[C:9]([N:8]2[C:3](=[O:25])[CH:4]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:5][C:6]2=[S:7])[S:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc(C(F)(F)F)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(Cc2ccccc2)NC(=S)N1c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of N-[[(4-trifluoromethyl-2-thiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (2.09 g, 5.38 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 1.01 g (53%) of the titled product:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](CC([O-])=O)=[CH:19][C:18]=2[CH3:27])=[CH:4][CH:3]=1.Cl.C[OH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:36])=[CH:19][C:18]=2[CH3:27])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1cc(CC(=O)[O-])ccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: Cl
Product: Cc1cc(O)ccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of [4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]-3-methylphenyl]acetate (4.30 g), 37% hydrochloride (3ml), and methanol (150 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, which was poured into a 10% aqueous solution of sodium hydrogen carbonate. The precipitated crystals were filtered, washed with pure water and air-dried to give crystals of 4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]-3-methylphenol (3.90 g, 99%). Recrystallization from tetrahydrofuran-hexane gave colorless prisms (2.56 g, 65%). Melting point 175-176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[N+:14]([O-])=O>O1CCCC1.CO.[Pd]>[NH2:14][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[N:12][CH:11]=[N:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(-c2cncnc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2cncnc2)cc1N
Yield: 184.6 %

Procedure:
A suspension of 5-(4-methyl-3-nitrophenyl)-pyrimidine (258 mg) in tetrahydrofuran (5ml) and methanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 130 mg) under hydrogen atmosphere for 4 hours. The catalyst was filtered off and the filtrate was evaporated to give 5-(3-amino4-methylphenyl)pyrimidine(410 mg, 96.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C@H:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17]1[C:21](S(C)(=O)=O)=[N:20][N:19]=[C:18]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C@H:13]([O:15][C:21]3[N:17]([CH3:16])[C:18]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[N:19][N:20]=3)[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)c1cc(-c2cccc(Cl)c2)on1
Reactant: Cn1c(-c2cccnc2)nnc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Oc1nnc(-c2cccnc2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 60 °C
Yield: 77.2 %

Procedure:
(1R)-1-[5-(3-chlorophenyl)isoxazol-3-yl]ethanol (5.40 g, 24.1 mmol) was dissolved in DMF (45 mL). To this 3-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine (5.75 g, 24.1 mmol) and cesium carbonate (10.1 g, 31.4 mmol) were added. After stirring over night at 60° C., water was added. The mixture was extracted with dichloromethane, followed by concentration of the organic layer in vacuo, to give a crude which was purified by column chromatography on silica using dichloromethane/methanol=98/2, to give the title compound (7.10 g, 77%). 1H NMR: 8.90 (d, 1H), 8.72 (m, 1H), 8.04 (dt, 1H), 7.76 (bs, 1H), 7.66 (m, 1H), 7.45 (m, 1H), 7.40 (m, 2H), 6.73 (s, 1H), 6.35 (q, 1H), 3.57 (s, 3H), 1.93 (d, 3H). 1H NMR (DMSO-d6): 8.90 (d, 1H), 8.71 (dd, 1H), 8.13 (dt, 1H), 7.99 (s, 1H), 7.86 (m, 1H), 7.58 (m, 3H), 7.40 (s, 1H), 6.19 (q, 1H), 3.54 (s, 3H), 1.81 (d, 3H). LC-MS (M++1)=382. [α]DRT (2.92 g/L, CDCl3)=−46.575°
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:34]=[CH:33][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27](=[O:32])[CH2:26]5)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH:40]=O>C(O)C.N1CCCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27](=[O:32])[C:26]5=[CH:40][C:36]4[NH:35][CH:39]=[CH:38][CH:37]=4)[CH:17]=3)=[O:14])=[CH:33][CH:34]=2)[CH2:6][CH2:7]1
Reactant: O=Cc1ccc[nH]1
Reactant: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)CC(=O)N5)c3)cc2)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)C(=Cc4ccc[nH]4)C(=O)N5)c3)cc2)CC1

Procedure:
To a solution of 4-(4-methyl-piperazin-1-ylmethyl)-N-[3-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-phenyl]-benzamide (23 mg, 0.05 mmol) in ethanol (2 ml) is added 1H-pyrrole-2-carbaldehyde (16 mg, 0.17 mmol) and 2 drops of piperidine. The reaction is refluxed for 12 hours and then concentrated. The desired compound after HPLC purification: 1H NMR (DMSO-d6) δ 2.44-2.52 (m, 2H), 2.79 (s, 3H), 2.98-3.10 (m, 2H), 3.18-3.22 (m, 2H), 3.38-3.42 (m, 2H), 3.77 (s, 2H), 6.32-6.36 (m, 1H), 6.61-6.69 (m, 111), 6.81-6.82 (m, 2H), 6.92 (dd, 1H, J=8.8 Hz, J2=1.6 Hz), 7.12-7.18, (m, 2H), 7.34 (s, 1H), 7.46 (dd, 2H, J=4.8 Hz, J2=1.6 Hz), 7.48 (s, 2H), 7.69 (s, 1H), 7.93 (d, 2H, J=8.0 Hz), 8.01 (s, 1H), 10.09 (s, 1H), 10.78 (s, 1H), 13.39 (s, 1H); LC-MS: 533.2 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1)=O.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C=O)cc1
Reactant: CC1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1CCCN1Cc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of tert-butyl 2-(4-formylphenyl)ethylcarbamate (3.0 g, 12.0 mmol), 2-methylpyrrolidine (1.44 ml, 14.4 mmol) and acetic acid (1.4 ml, 24.0 mmol) in THF (100 ml) was added sodium triacetoxyborohydride (5.1 g, 24.0 mmol), and the mixture was stirred at room temperature for 16 hrs. 10% Sodium hydrogencarbonate solution (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated brine, and dried over magnesium sulfate, and solvent was evaporated under reduced pressure. The residue was purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give the title compound (3.10 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[N:10].[C:11]([C:15]1[C:24]2[O:23][CH2:22][CH2:21][NH:20][C:19]=2[CH:18]=[C:17]([C:25](=[O:27])[CH3:26])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>CN(C)C=O>[C:25]([C:17]1[CH:16]=[C:15]([C:11]([CH3:14])([CH3:12])[CH3:13])[C:24]2[O:23][CH2:22][CH2:21][N:20]([CH2:8][C:9]#[N:10])[C:19]=2[CH:18]=1)(=[O:27])[CH3:26]
Reactant: N#CCBr
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2CC#N
Temperature: 90 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
Potassium carbonate (3.6 g, 26 mmol) and bromoacetonitrile (15.4 g, 128.6 mmol) were added to a solution of 1-[8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (6.0 g, 25.5 mmol) in dimethylformamide (100 ml) and the mixture was stirred at 90° C. for 6 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (6.9 g) as a light yellow oil.
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1Cl)NC(=O)CN2
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A solution of N-(4'-chloro-5'-methyl-2'-nitrophenyl)glycine sodium salt (0.300 g, 1.23 mmol, as prepared above) and tin (II) chloride dihydrate (0.830 g, 3.68 mmol, Aldrich, used as received) in ethanol (4.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the precipitated solid was filtered, washed with ethanol (1.0 mL) and dried under vacuum to yield 0.160 g (66%) of the title compound as a yellow powder; 1H NMR (DMSO-d6): δ2.099 (s, 3H), 3.655 (s, 2H), 6.037 (s, 1H), 6.538 (s, 1H), 6.685 (s, 1H), 10.241 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]>CCOCC.N1C=CC=CC=1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][C:20]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[CH:21][CH:16]=1
Reactant: COc1ccccc1I
Reactant: c1ccc2occc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(-c2cc3ccccc3o2)cc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
A solution of 46.0 g (0.39 mole) of benzofuran in 100 mL of Et2O was treated with 0.40 mol (1.6 M in hexanes) of n-BuLi at such a rate as to keep the reaction temperature below 25° C. The mixture was stirred for 15 min and was added to a 10° C. solution of 57.2 g (0.40 mole) of CuBr in 100 mL of Et2O at a rate so as to keep the reaction temperature below 10° C. The mixture was allowed to reach room temperature over 0.5 h and was treated with a solution of 93.6 g of iodoanisole in 300 mL of pyridine. The mixture was heated to 110° C. for 3 h, allowing the Et2O to boil off. The reaction mixture was concentrated in vacuo and the residue was dissolved in 3 L of EtOAc. The organic layer was washed several times with 2 N aqueous HCl and once with H2O, dried over MgSO4, and filtered. Concentration in vacuo afforded a residue which was recrystallized from MeOH to afford 44.5 g of the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][C:25]3[N:26]=[C:22]([CH3:21])[S:23][C:24]=3[CH:30]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cc1nc2ccc(C=O)cc2s1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2nc(C)sc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-methylbenzo[d]thiazole-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 397.02 g/mol.