Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:22])[NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=1)[CH2:2][CH3:3].Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][N:25]=1.N1CCOCC1>>[O:33]1[CH2:34][CH2:35][N:30]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:22])=[CH:12][CH:11]=3)[N:29]=2)[CH2:31][CH2:32]1
Reactant: CCCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1nccc(N2CCOCC2)n1
Solvent: C1COCCN1
Product: CCCNC(=O)Nc1ccc(-c2nccc(N3CCOCC3)n2)cc1

Procedure:
Method as described for Example 34 using (4-(3-propylureido)phenyl)boronic acid pinacol ester and 4-(2-chloropyrimidin-4-yl)morpholine which was synthesised according to Intermediate 3, using morpholine as starting material.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[N:13]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:12]=2)[CH:2]=1.Br[C:37]1[S:38][C:39]([S:42][CH3:43])=[N:40][N:41]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[CH3:43][S:42][C:39]1[S:38][C:37]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH:12]=[C:11]3[C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:41][N:40]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cnc3ccccc3c2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CSc1nnc(Br)s1
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: O
Product: CSc1nnc(-c2ccc3c(c2)c(-c2cnc4ccccc4c2)cn3C(=O)OC(C)(C)C)s1
Temperature: 120 °C
Yield: 50.8 %

Procedure:
A mixture of tert-butyl 3-(quinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (80 mg, 170 μmol), 2-bromo-5-(methylthio)-1,3,4-thiadiazole (54 mg, 255 μmol), Pd(PPh3)4 (9.8 mg, 8.5 μmol) and potassium carbonate (71 mg, 510 μmol) in dioxane (1.0 mL) was added H2O (0.2 mL). The reaction was heated in a microwave at 120° C. for 70 min. The solvent was then removed and the residue was purified with silica gel chromatography to give tert-butyl 5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-3-(quinolin-3-yl)-1H-indole-1-carboxylate (41 mg, 51%). MS (ESI, pos. ion) m/z: 475 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][CH2:16][C:17](OCC)=[O:18].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:17](=[O:18])[CH2:16][O:15][CH3:14])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)COC
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCC(=O)C(C#N)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl (methyloxy)acetate (1.65 g, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) to remove all non-basic organic impurities, and then it was acidified to pH of 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-4-(methyloxy)-3-oxobutanenitrile as a brown oil (1.8 g, 7.2 mmol, 66% yield), MS (EI) for C13H15NO4: 250 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][O:10][S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
The recovered intermediate (20a) (8.5 g, 33 mmol, 1.0 eq) was dissolved into 70 mL pyridine containing potassium hydroxide (2.1 g, 37 mmol, 1.1 eq) and the mixture was chilled in an ice bath. Tosyl chloride (7.1 g, 37 mmol, 1.1 eq) was added and the mixture was stirred at 0° C. for 2 hours then refrigerated overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The recovered residue was dissolved into 300 mL EtOAc, washed with 2×200 mL 1M H3PO4, saturated bicarbonate, and saturated aqueous NaCl. The organic was dried over MgSO4 and concentrated under reduced pressure to yield intermediate (20b) (10.3 g) as a pale brown oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])=[O:29]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33]([C:32]4[CH:31]=[C:30]([CH:38]=[CH:37][CH:36]=4)[C:28]([O:27][CH3:26])=[O:29])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(methoxycarbonyl)benzoic acid as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OO)(C)(C)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:5]2[C:10]([C:11](=[O:24])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)C(=O)N(C)C
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OO
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC1=CC(=O)c2ccccc2C1(CCC(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 169B (190 mg, 0.63 mmol) in benzene (4 mL) at room temperature under a N2 atmosphere was added 200 mg Celite® and pyridinium dichromate (474 mg, 1.26 mmol) followed by 70% tert-butyl hydroperoxide (175 μL, 1.26 mmol). The mixture was allowed to stir at room temperature for 1 hour, filtered through a pad of Celite® and the filtrate added to ethyl acetate (10 mL). The organic solution was washed with 5% Na2S2O5 (3× 10 mL) and with saturated NaCl (1× 10 mL) and dried over Na2SO4. The crude product was purified by column chromatography using 50% ethyl acetate in hexane. The title compound was obtained as a colorless oil (59 mg, 30%). 1H NMR (300 MHz, CDCl3): δ 8.18 (d, 1H), 7.56 (t, 1H), 7.44 (t, 1H), 7.26 (d, 1H), 5.98 (s, 1H), 3.85 (s, 3H), 2.95, 2.39 (dm, 3H), 2.42, 2.21 (dm, 2H), 1.56 (s, 3H), 1.32 (m, 1H), 0.73 (d, 3H), 0.65 (d, 3H), 0.28 (m, 2H). MS (ESI) m/z=316 [M+H].
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][C:20](Cl)=[C:15]2[CH:14]=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(=O)C>CN(C)C=O>[N:1]([C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[N:12]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:13]=[CH:14][C:15]=12)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccnc2c1cnn2Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1ccnc2c1cnn2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
Sodium azide (2.5 g) was added to a solution (50 ml) of 1-benzyl-4-chloro-1H-pyrazolo[3,4-b]pyridine (4.7 g) in dimethylformamide and the mixture was stirred at 100°-120° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water, made acidic with acetic acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 2.7 g of 4-azido-1-benzyl-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Br[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(Nc2ccc(F)cc2F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(N(c2ccc(C=O)cc2)c2ccc(F)cc2F)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4-butyl-N-(2,4-difluorophenyl)benzeneamine (30 m mol)), 4-bromobenzaldehyde (34 m mol)), tris(dibenzylideneaceton)dipalladium(O) (0.5 m mol)), tris-tert-butylphosphine (0.9 m mol)), and sodium-tert-butoxide (40 m mol)) were dissolved in toluene (100 ml) in a 250 ml tri-neck-round bottom flask and then stirred in a bath of 100° C. for 24 hours. After the reaction was terminated, the toluene was removed from the solution. After extraction was performed on the solution using dichloromethane and water, reduced pressure and distillation were performed on the resulting solution. After a silica gel column chromatography, the solvent was reduced in pressure and distilled, thereby obtaining 4-(N-(4-butylphenyl)-N-(2,4-difluorophenyl)amino)benzaldehyde liquid having 7.1 g.
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[CH3:28])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH:39]=2)[CH:33]=1)(C)(C)C.FC(F)(F)C(O)=O.[ClH:54]>C(Cl)Cl>[Cl:54][C:22]1([CH3:28])[CH2:23][CH:24]=[CH:25][CH:26]=[C:21]1[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:46])=[O:5])=[C:8]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH:39]=4)[CH:33]=3)[CH:9]=2)=[O:29])=[CH:20][CH:19]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(NC(=O)c2ccc(C(=O)OC(C)(C)C)c(CCc3cccc(C4=CCC(C)(C)CC4)c3)c2)cc1
Reactant: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cccc(CCc3cc(C(=O)Nc4ccc(C5=CC=CCC5(C)Cl)cc4)ccc3C(=O)O)c2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 4-{4′-chloro-2′-methyl-biphenyl-4-ylcarbamoyl)-2-[(3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethyl}-benzoic acid tert-butyl ester (0.82 g, 1.29 mmol) in CH2Cl2 (30 mL) at room temperature, added trifluoroacetic acid (2.5 ml), and conc HCl (1.0 mL) The reaction mixture was stirred overnight. The organic solvents were removed under reduced pressure. The residue was extracted with ethyl acetate (2×100 mL), dried over MgSO4 and concentrated o afford 4-{2′-chloro-2′-methyl-biphenyl-4-ylcarbamoyl)-2-[(3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethyl}-benzoic acid as a solid. 1H NMR (500 MHz, DMSO-d6): 10.05 (s, 1 H), 7.73 (d, J=8.0 Hz, 2 H), 7.48 (d, J=8.5 Hz, 2 H), 7.40 (s, 1 H), 7.29-7.05 (m, 10 H), 5.99 (s, 1 H), 3.96 (t, J=10.5 Hz. 1 H), 2.95 (dd, J=5.0, 14.0 Hz, 1 H), 2.20-2.18 (m, 1 H), 2.14 (t, J=7.5 Hz, 1 H), 2.09 (s, 3 H), 1.89 (bs, 2 H), 1.49 (t, J=7.5 Hz, 1 H), 1.39 (t, J=6.0 Hz, 2 H), 0.84 (s, 6 H). Chiral HPLC conditions: Chiralcel OD-H T=23° C.; mobile phase=10-30% hexane/IPA; flow rate=1.0 mL/min; detection=254, 280, 220 nm retention time in min: 19.81 min (enantiomeric excess: 70.8%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]#[N:24])=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: N#Cc1ccccc1B(O)O
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: COCCOC
Solvent: O
Product: N#Cc1ccccc1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 32.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.023 g (33%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:23]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:21]([O:20][CH3:19])[CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: COc1ccc(N)cc1OC
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC)c(OC)c1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (89 mg, 0.3 mmol) was treated with 3,4-dimethoxy-aniline following general procedure B to afford 4-(3,4-dimethoxy-phenylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (103 mg). Thus obtained amino-ester (38 mg, 0.1 mmol) was subjected to reaction with ethyl isocyanate (0.5 mmol) according to general procedure C to furnish 1-(3,4-dimethoxy-phenyl)-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (23 mg). LCMS: m/z 408 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.64 (s, 1H), 7.11 (m, 2H), 7.00 (s, 1H), 6.91 (m, 2H), 6.60 (s, 1H), 4.20 (q, 2H), 4.09 (s, 3H), 3.99 (s, 3H), 3.86 (s, 3H), and 1.37 (t, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:23])[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1.[C:29]([Cu])#[N:30].[C-]#N.[Na+]>CN(C=O)C>[C:29]([C:2]1[CH:3]=[C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:23])[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)#[N:30]
Reactant: Cc1ccc(C(=O)c2ccc(Cc3ccc(NS(C)(=O)=O)cc3Br)n2C)cc1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc(NS(C)(=O)=O)cc3C#N)n2C)cc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
N-{3-Bromo-4-[5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-ylmethyl]phenyl}methanesulfonamide (320 mg, 0.69 mmol) was dissolved in DMF. CuCN (120 mg, 1.38 mmol) was added and the suspension was refluxed for 4 h. The mixture was cooled to room temperature, and NaCN (2.0 g in 10 ml of water) was added. After 0.5 h the mixture was extracted with ethyl acetate and the extracts were washed with water, and brine, and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparatory TLC (hexane-ethyl acetate) to give N-{3-cyano-4-[5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-yl-methyl]phenyl}methanesulfonamide (190 mg, 67%) as a solid, mp 171-172° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].O>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: Nc1ccccc1Cl
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CNc2ccccc2Cl)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (5 g) and 2-chloroaniline (2.5 mL) in toluene (60 mL) is heated at reflux under a Dean and Stark water trap for 3 hours. After concentration, the residue is dissolved in methanol (60 mL) and the stirred solution is treated at 0° C. with sodium cyanoborohydride (2.1 g). The temperature is allowed to rise to room temperature, and the stirring is continued for 2 hours, before dilution with ethyl acetate (100 mL) and washing with saline (100 mL). The organic layer is dried and concentrated, to give a brown oil. This oil is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1:4 v/v), to give N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzylamine (0.64 g), in the form of an oil. [Elemental analysis: C, 69.5; H, 6.8; N, 4.1; Cl, 10.6%; calculated: C, 68.8; H, 6.7; N, 3.2; Cl, 10.7%].
Reaction SMILES: [C:1]([C:9]([OH:11])=[O:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:15])=[O:14].S(=O)(=O)(O)O>C(O)(=O)C>[C:2]1([C:1]2[C:9](=[O:10])[O:11][C:13]3([CH:15]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:10])[O:14]3)[CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(O)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1OC2(C=C1c1ccccc1)C=C(c1ccccc1)C(=O)O2
Temperature: 25 °C

Procedure:
Benzoylformic acid, 25 g, and 11.25 g of acetone in 30 g of acetic acid and 45 g of concentrated sulfuric acid were heated at 105° C.-110° C. for 1 hour. After the resulting mixture was cooled to ambient temperature, it was poured onto ice and the mixture was allowed to warm to room temperature. The suspended particles were recovered by filtration and recrystallized from ethanol to give 3,8-diphenyl-2,7-dioxo-1,6-dioxaspiro[4.4]nona-3,8-diene, m.pt. 235°-237° C., as white powder. Infrared and nuclear magnetic resonance spectra of the powder were consistent with this structure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([NH:14][C:15]3[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[O:36])=[O:20])=[CH:17][C:16]=3[O:47][CH3:48])=[O:13])[C:5]=2[N:4]=1.C(N(CC)CC)C.CS(C)=O.C(=O)(O)[O-].[Na+]>O.ClCCl>[CH:2]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([NH:14][C:15]3[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[O:36])=[O:20])=[CH:17][C:16]=3[O:47][CH3:48])=[O:13])[C:5]=2[N:4]=1)=[O:1]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CO)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C=O)nc12
Reaction time: 24 h
Yield: 15 %

Procedure:
To a mixture of 4-(2-hydroxymethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (40 mg), triethylamine (31 mg), dimethyl sulfoxide (0.5 ml) and dichloromethane (0.5 ml) was added portionwise sulfur trioxide pyridine complex (29 mg) in water bath and the mixture was stirred at the same temperature for 1 day. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and the solution was extracted with chloroform. The organic layer was washed with water and brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-formyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (6 mg) as a powder.
Reaction SMILES: N#N.Cl[C:4]1[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][N:9]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1>O.O1CCOCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:5]2[C:4]([C:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=3)=[N:9][CH:8]=[CH:7][N:6]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: N#N
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a N2 purged solution of N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (4.891 g, 16.37 mmol), potassium acetate (6.54 g, 66.6 mmol), dioxane:water (160 mL, 10:1), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (6.03 g, 19.50 mmol) was added A-Phos (1.5 g, 2.118 mmol). The vial was capped and placed in a preheated oil bath (120° C.) and stirred for 1.5 hours. The solution was allowed to cool to room temperature and poured into water. The aqueous solution was extracted with EtOAc (3×70 mL). The combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with 0% to 50% EtOAc in hexane, to provide tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow foam. MS (ESI, pos. ion) m/z: 446.1 (M+1). IC50 (uM) 0.01298.