Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[S:20]1[C:24]([C:25](O)=[O:26])=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2.C(=O)([O-])O.[Na+]>O>[S:20]1[C:24]([C:25]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:17])[F:18])=[O:26])=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCOC(=O)c1cc2ccccc2s1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To 40 ml of N,N-dimethylformamide were dissolved 5.00 g (22 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 4.30 g (24 mmol) of benzo[b]thiophene-2-carboxylicacid, followed by the addition of 6.00 g (71 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 5.50 g (yield: 81%) of 6,6-difluoro-5-methyl-5-hexenyl benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]2[CH:20]=[C:21](Br)[S:22][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.Cl>C(O)C.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]2[S:22][C:21]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:20][C:9]1=2
Reactant: OB(O)c1cccs1
Reactant: CCOC(=O)c1cc2sc(Br)cc2n1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc2sc(-c3cccs3)cc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.4 %

Procedure:
Tetrakis-(triphenylphosphine)palladium (0) (20 mg) was added to a degassed solution of ethyl4-(3,4-dichlorobenzyl)-2-bromothieno[3,2-b]pyrrole-5-carboxylate (0.1 g) and thiophene-2-boronic acid (34 mg) in ethanol (1 ml), toluene (1 ml) and aqueous potassium carbonate (2N, 1 ml), and the reaction stirred at 80° C. under an argon atmosphere for 6 hours. The reaction was cooled, poured into 2N HCl and extracted with ether. Combined organic extracts were cried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using isohexane to isohexane-25% ethyl acetate as eluent to give the product as a pale yellow crystalline solid (77 mg, 77%), M/z (+) 435 (MH+), 276, 204, 159, 127.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH:16]3[C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=2)[O:3]1.[Li+].[OH-]>C1COCC1.O>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:23])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH:16]3[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[O:5]1
Reactant: CCOC(=O)C1CC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(C3CC3C(=O)O)cc2)OC1(C)C
Reaction time: 18 h

Procedure:
To a solution of ester from step 2 in THF-H2O (0.2M) was added LiOH (3 eq, 2M) and the mixture was stirred at it for 18 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford the title carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:22]2[C:30]3[N:29]=[C:28]([O:31]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:25]=[C:24]([C:41]3[C:42]([CH3:47])=[N:43][O:44][C:45]=3[CH3:46])[CH:23]=2)=[O:21])=[N:18][CH:19]=1.Cl>O1CCCC1.C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:21])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:22]2[C:30]3[NH:29][C:28](=[O:31])[NH:27][C:26]=3[CH:25]=[C:24]([C:41]3[C:42]([CH3:47])=[N:43][O:44][C:45]=3[CH3:46])[CH:23]=2)=[N:18][CH:19]=1
Reactant: CCOc1nc2c(C(=O)c3ccc(Cl)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: Brc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)c2ccc(Cl)cn2)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To 2-bromopyridine (0.02 ml, 0.2 mmol) in tetrahydrofuran (4 mL) at −78° C. was added n-butyllithium (0.15 mL, 0.24 mmol, 1.6 M in hexanes). After 30 minutes, tert-butyl 4-(5-chloropicolinoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate (33 mg, 0.07 mmol) in tetrahydrofuran (1 mL) was added drop-wise to the reaction. After 30 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (3 mL) was added hydrochloric acid (0.17 mL, 0.66 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (23-40% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 4-((5-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1)(=[O:31])[C:28]([CH3:30])=[CH2:29]
Reactant: CC(C)=C1C(=O)N(c2ccc(N)cc2)C(=O)/C1=C(\C)c1cc(C)oc1C
Reactant: C=C(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(C)oc3C)C2=O)cc1
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution obtained by dissolving 105 mg of N-(4-aminophenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 1 in 2 ml of chloroform, 5 ml of pyridine was added, followed by dropwise addition of 0.84 ml of methacryloyl chloride in 10 minutes. The reaction was carried out at room temperature for additional 4 hours with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to the removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give yellow crystals of N-(4-methacryloylaminophenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethyliden]-3-isopropylidenesuccinimide in yield of 40.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.O[C:14]([C:17](O)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]2[O:9][C:17]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:15])[O:10]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: CC(C)(O)C(C)(C)O
Product: COc1ccc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Yield: 57 %

Procedure:
The title compound (57%, oil) was prepared from 5-chloro-2-methoxyphenylboronic acid and pinacol.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:22].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:22])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1cc(OC)ccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3ccc(OC)cc3nc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-4-methoxyanthranilic acid (13.3 g, 0.051 mol) and POCl3 (125 ml) was refluxed for 3 hours, then was allowed to sit overnight. The volume of POCl3 was reduced, then ice/water, followed by NH4OH was added. A precipitate formed which was collected by filtration and dried in a vacuum oven at 50° C. to afford 11.51 g (87%) of 1-ethyl-4-chloro-7-methoxy-1H-pyrazolo[3,4-b]quinoline, m.p. 95-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=O)=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:53]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20]([Cl:53])=[N:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)n1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Fc1ccc(C2CC(C(Cl)=Nc3ccc(C(F)(F)F)cc3)=NN2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.2 %

Procedure:
To a solution of 2.50 g (0.0054 mol) of 1-(4-chlorophenyl)-5-(4-fluorophenyl)-N-[4-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxamide dissolved in 15 mL of acetonitrile was added 1.80 g (0.0067 mol) of triphenylphosphine and 0.83 g (0.0054 mol) of carbon tetrachloride. The yellow solution was stirred at room temperature overnight and concentrated to afford 4.0 g of a yellow solid. The crude product was chromatographed on silica gel using ethyl acetate (10%) and hexanes (90%) as eluents which afforded 0.64 g of a yellow solid, mp 154° C. to 156° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:12])[O:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OCc1cccnc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)OCc1cccnc1
Reaction time: 2 h
Yield: 99 %

Procedure:
p-Nitrophenylisocyanate (0.1 mole) was added to a solution of 3-pyridylcarbinol (0.1 mole) in 300 ml. of benzene. An exothermic reaction took place and a yellow solid formed. The suspension was heated to reflux and then stirred for 2 hours. The suspension was then cooled and filtered, affording 27 g. of a crude product melting at 230°-231° C. (decomposed). This is a 99% yield of 3-pyridylmethyl N-(4'-nitrophenyl)-carbamate. The product was purified by recrystallization from 2-methoxyethanol (methyl Cellosolve).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[NH2:14][NH2:15]>C1COCC1>[NH:14]([C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1)[NH2:15]
Reactant: CCOC(=O)c1cnc(Cl)nc1C
Reactant: NN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1C
Yield: 93 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (0.08 g, 0.39 mmol) and hydrazine (0.06 g, 2.0 mmol) in THF (7.8 mL) resulting in a 93% yield (0.07 g); 1H NMR (CDCl3) δ 8.86 (s, 1H), 6.64 (bs, 1H), 4.33 (q, 2H), 2.70 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.O>CO>[CH:12]1([NH:15][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: ClCCCOc1cccnc1
Solvent: O
Solvent: CO
Product: c1cncc(OCCCNC2CC2)c1
Temperature: 120 °C
Yield: 29.3 %

Procedure:
An Ace Glass pressure tube (185 mL) was charged with 3-chloro-1-(3-pyridyloxy)propane (0.762 g, 4.437 mmol), cyclopropylamine (8.24 g, 194.3 mmol), water (20 mL) and methanol (20 mL). The resulting light-brown solution was heated at 120° C. (oil bath temperature) for 2.5 h and allowed to cool to ambient temperature over 16 h. The solution was concentrated by rotary evaporation to an oily residue that was diluted with saturated NaCl solution (25 mL). The mixture was acidified to pH 1.0 with 10% HCl solution and extracted with CHCl3 (2×35 mL) to remove impurities. The aqueous phase was basified to pH 6 with 10% NaOH solution and extracted (4×25 mL) to remove other impurities. The aqueous phase was basified to pH 10 with 10% NaOH solution and extracted with CHCl3 (4×50 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated (rotary evaporator) and briefly dried under high vacuum to give 0.250 g of a brown oil. The oil was purified by column chromatography on silica gel (20 g) eluting with CHCl3—CH3OH (100:2) to remove impurities, followed by CHCl3—CH3OH-Et3N (50:50:2) to remove the product. Selected fractions were combined to give 220 mg (25.8%) of a brown semi-solid.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH3:30])[C:9]([CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][N:17]=2)=[N:10][CH:11]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:7]=[C:8]([CH3:30])[C:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:16]3=[N:17][CH:18]=[C:19]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:20]=[C:21]3[N:22]=[N:1]2)=[N:10][CH:11]=1
Reactant: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Br)cnc1CCCn1nnc2cc(Cc3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Sodium nitrite solution (1.02 g in 50 ml water) was added dropwise over 25 minutes to a stirred and cooled solution of 2-[3-(5-bromo-3-methylpyrid-2-yl)-propylamino]-3-amino-5-(pyrid-3-ylmethyl)pyridine (4.7 g) in sulphuric acid (molar, 200 ml) keeping the temperature at 4° C. Reaction was stirred at 4° C. for a further hour and was then left in the fridge overnight and then warmed to room temperature. The reaction mixture was basified to pH 13 with sodium hydroxide solution (10 M). Chloroform extraction of the reaction mixture gave the crude product which was then chromatographed on silica in methanol/chloroform 1:19 and then recrystallised from acetonitrile to give the title compound (2.75 g), m.p. 109°-110° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[N:4]=1.C(OC(=O)C)(=O)C.[Br:18]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][S:2][C:3]1[C:8]([Br:18])=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1cc(C)[nH]c(=O)n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSc1nc(=O)[nH]c(C)c1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35 %

Procedure:
4-Methylthio-6-methylpyrimid-2-one (see Wheeler, L. H. and MacFarland, F. D. J. Amer. Chem. Soc. 42 (1909) (43) (0.01 mol) was dissolved in acetic acid (30 ml) containing 2% acetic anhydride and N-bromo-succinimide (0.013 mol) added. The reaction mixture was kept at 55° C. for 40 min. Ice-cold water (150 ml) containing a little sodium bisulphite was added to the cold reaction mixture. The precipitate formed was recrystallised from water; yield 35%, m.p. 244° C. (Found: C, 30.34; H, 2.81. Calc. for C6H7BrN2OS: C, 30.65; H, 3.00).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[N:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>CCCCCC>[CH2:1]([N:8]1[C:9]2=[N:13][C:14]3[C:15]([C:16]([NH2:17])=[C:10]2[CH2:11][CH2:12]1)=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1N=C1CCCN1Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1c2c(nc3ccccc13)N(Cc1ccccc1)CC2
Temperature: -10 °C
Yield: 37.9 %

Procedure:
The compound 1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamine (Compound 25) was synthesized by first cooling a solution of Compound 24 (37.6 g, 0.14 mol) and tetrahydrofuran (350 mL) to −35° C. under argon atmosphere and adding a solution of hexane (110 mL) and lithium diisopropylamine-tetrahydrofuran complex (0.35 mol) dropwise. The temperature of the mixture was then gradually raised to −10° C. and ice-water (30 mL) was added dropwise. Organic solvent was evaporated under reduced pressure and the mixture was extracted with chloroform. The combined organic extracts were dried with anhydrous sodium sulfate and condensed under vacuum. The residue was treated with ethanol (15 mL) and crystals precipitated. The precipitate was filtered, washed with cold ethanol and dried under vacuum to yield 14.6 g (39%) of Compound 25 as needles; mp 174-176° C.; IR (KBr): 3411, 3116, 1654, 1502, 1350, 756 cm−1; 1H NMR (DMSO-d6): δ 7.01-7.93 (m, 9H), 6.05 (s, 2H), 4.60 (s, 2H), 3.37 (t, 2H), 2.87 (t, 2H); 13C NMR (CDCl3): δ 162.7, 149.3, 144.8, 138.8, 128.7, 128.2, 128.1, 127.2, 126.2, 121.8, 119.9, 117.6, 100.7, 48.4, 23.3. Anal. Calcd. for C18H17N3(275.35): C, 78.52; H, 6.22; N, 15.26. Found: C, 78.07; H, 6.07 N, 15.08;
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12].[NH2:16][C:17]1[N:22]=[C:21](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:20]([CH2:36][C:37]2[CH:52]=[CH:51][C:40]([CH2:41][N:42]([CH2:49][CH3:50])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][C:38]=2[O:53][CH3:54])=[C:19]([CH3:55])[N:18]=1>C(#N)CC>[NH2:16][C:17]1[N:22]=[C:21]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:20]([CH2:36][C:37]2[CH:52]=[CH:51][C:40]([CH2:41][N:42]([CH2:49][CH3:50])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][C:38]=2[O:53][CH3:54])=[C:19]([CH3:55])[N:18]=1
Reactant: CCC[C@H](N)CCO
Reactant: CCOC(=O)CN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCC#N
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC)CC(=O)OCC)cc1OC
Temperature: 120 °C
Yield: 78.8 %

Procedure:
Trifluoroacetic acid (0.066 mL) was added to a mixture of (S)-3-aminohexan-1-ol (300 mg) and the product from step (vii) (490 mg) in propionitrile (5 mL). The mixture was heated at 120° C. for 16 h and cooled to RT. The solvent was removed by evaporation. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (330 mg) as a colourless gum; 1H NMR (CDCl3); 6.94 (1H, s), 6.88 (1H, d), 6.79 (1H, d), 4.66 (1H, d), 4.58 (2H, br s), 4.13 (2H, q), 4.11-4.06 (1H, m), 3.88 (3H, s), 3.70 (2H, s), 3.66 (2H, s), 3.42 (1H, ddd), 3.28-3.20 (3H, m), 2.65 (2H, q), 2.34 (3H, s), 1.82-1.74 (1H, m), 1.45-1.33 (1H, m), 1.26-1.21 (5H, m), 1.07-1.02 (5H, m), 0.73 (3H, t).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:35](=[CH:36][CH:37]=2)[O:34][C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]5[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[O:19])[CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:38])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:39][C:40](OC(C)=O)=[O:41].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:35](=[CH:36][CH:37]=2)[O:34][C:12]2([CH2:13][CH2:14][N:15]([C:18]([C:20]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]5[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[O:19])[CH2:16][CH2:17]2)[CH2:11][C:10]3=[O:38])[CH2:2][CH2:3]1)(=[O:41])[CH3:39]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N4CCNCC4)ccc2O3)nc2c(OC)cccc12
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N4CCN(C(C)=O)CC4)ccc2O3)nc2c(OC)cccc12
Reaction time: 4 h

Procedure:
To a solution of 165 mg of 6-(piperazin-1-yl)-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one in 2 mL of CHCl3 was added 0.165 mL of Ac2O and 0.33 ml of triethylamine and the mixture was stirred for 4 hrs. The mixture was partitioned between CHCl3 and 1N NaOHaq, and the organic layer was separated, washed with brine, dried over MgSO4, and concentrated. The residue was purified on preparative TLC (SiO2, CHCl3/MeOH=9/1) to afford the intended compound as a yellow powder. 1H-NMR (400 MHz, CDCl3) δ7.74 (1H, d, J=8.4 Hz), 7.45 (1H, ddd, J=8.4, 8.0, 0.8 Hz), 7.32-7.34 (1H, m), 7.18 (1H, dd, J=8.8, 1.4 Hz), 7.16 (1H, s), 7.06 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=8.8 Hz), 4.50-4.60 (1H, m), 4.00-4.20 (1H, m), 4.06 (3H, s), 4.02 (3H, s), 3.70-3.80 (2H, m), 3.50-3.70 (3H, m), 3.33-3.40 (1H, m), 3.00-3.20 (4H, m), 2.78 (1H, d, J=16.8 Hz), 2.72 (1H, d, J=16.8 Hz), 2.21-2.30 (1H, m), 2.10-2.20 (1H, m), 1.70-2.95 (2H, m). MS [M+H]+=559.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([CH3:13])=[CH:5][C:4]=1Br.CCCCCC.C([Li])CCC.[CH2:26]([Si:28]([CH2:31]C)(Cl)[Cl:29])C>C(OCC)C>[CH3:1][O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([CH3:13])=[CH:5][C:4]=1[Si:28]([Cl:29])([CH3:31])[CH3:26]
Reactant: COc1c(Br)cc(C)cc1C(C)(C)C
Reactant: CC[Si](Cl)(Cl)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 2-methoxy-1-bromo-3-tert-butyl-5-methylbenzene (20.00 g, 77.77 mmol) was dissolved in 200 mL of diethyl ether. A 1.57 M hexane solution of n-butyllithium (59.44 mL, 93.32 mmol) was dropwise added at −50° C. or lower, and a temperature was raised to room temperature, followed by stirring for 1 hour. All the amount of diethyldichlorosilane (24.44 g, 155.54 mmol) was added to the mixture at once at −50° C. or lower, and a temperature was gradually raised to room temperature. After being refluxed for 1 hour, the solution was concentrated under reduced pressure. Hexane was added, the insolubles were filtered off with a Celite filter, and the filtrate was concentrated under reduced pressure. Concentration was further continued at 70° C. under reduced pressure for 3 hours to obtain (2-methoxy-3-tert-butyl-5-methylphenyl)chlorodimethylsilane. Resultant (2-methoxy-3-tert-butyl-5-methylphenyl)chlorodimethylsilane was used in a subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:51]6[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]6)[CH:42]=5)[C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)n1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCNCC4)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-2,6-pyridinedicarboxamide (40.0 mg. 0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing piperazine (0.178 mmol) and acetic acid (0.059 mmol, 3.55 mg) and with fitted magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.592 mmol, 138 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and purification was completed via a Gilson HPLC (basic conditions) to afford 8.32 mg of the title compound (18.9%). LC-MS m/z 746 (M+H)+, 1.27 min (ret time).