Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:36].C(O)(=O)C(O)=O>[Cu]I.CN(C=O)C>[CH:38]1([NH:37][C:35](=[O:36])[CH2:34][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)NC1CCCCC1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [Cu]I
Agent: O=C(O)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)NC2CCCCC2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. CuI (9 mg, 0.045 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) was added to the solution and stirred for 10 min. at RT. 2-chloro-N-cyclohexylacetamide (98 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. And purified by column chromatography and then oxalate salt was made by using oxalic acid (35 mg, 0.46 mmol) to obtain 100 mg of N-cyclohexyl-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide as the oxalate salt.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:24]([C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[CH:31]=O)([CH3:27])([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>CO>[CH3:40][C:37]([C:34]1[CH:33]=[C:30]([CH2:31][N:15]2[CH2:16][CH2:17][N:12]([C:10]3[CH:9]=[C:8]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[N:7]=[C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:11]=3)[CH2:13][CH2:14]2)[CH:29]=[C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:35]=1[OH:36])([CH3:38])[CH3:39]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(CN2CCN(c3cc(N4CCCC4)nc(N4CCCC4)n3)CC2)cc(C(C)(C)C)c1O
Reaction time: 18 h

Procedure:
2,6-bis(1-pyrrolidinyl)-4-(1-piperazinyl)pyrimidine (PREPARATION A-22) is stirred in methanol (10 ml). To the above solution is added saturated ethereal hydrochloric acid until the solution clarifies. To this mixture is added 3,5-di-t-butyl-4-hydroxybenzaldehyde and the mixture stirred for 30 min at which time sodium cyanoborohydride is added in two batches. The mixture is stirred at 20°-25° for 18 hr and quenched with hydrochoric acid (10%, 25 ml) added dropwise at 0°. The methanol is removed under a stream of nitrogen and the acidic mixture is extracted with ethyl acetate (25 ml). The aqueous phase is then made basic with hydroxide (45%) at 0°. The aqueous basic phase is then extracted with methylene chloride (2×). The organic phases are combined and dried over sodium sulfate, following which the mixture is concentrated under at reduced pressure. The concentrate is flashed chromatographed on silica gel eluting with hexane/ethyl acetate (1/1) or ethyl acetate. The appropriate fractions are pooled and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]([CH3:11])[N:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:22][C@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@@H:23]2[CH3:22])[C:5]2[N:10]([CH3:11])[N:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cn1ncc2nc(Cl)nc(Cl)c21
Reactant: C[C@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H]1COCCN1c1nc(Cl)nc2cnn(C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a stirred solution of 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (200.0 mg, 0.98 mmol) in anhydrous DMF (2 mL) was added N,N-diisopropylethylamine (0.21 mL, 1.18 mmol, 1.2 eq.) followed by (S)-3-methylmorpholine (199.3 mg, 1.9 mmol, 2.0 eq.). The reaction mixture was stirred at RT under N2 for 4 h and diluted with ether (50 mL). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in heptane) to afford the desired product (k-1) as a foam (245.4 mg, 93.0%). 1H NMR (CDCl3, 500 MHz) δ ppm 8.03 (s, 1H), 4.21 (broad d, J=6.2 Hz, 1H), 4.15 (s, 3H), 3.97 (d, J=10.7 Hz, 1H), 3.90 (d, J=9.8 Hz, 1H), 3.81 to 3.65 (m, 3H), 3.56 (d, J=12.4 Hz, 1H), 1.38 (d, J=6.6 Hz, 3H); LC-MS m/z (method A)=268 [M+H]+, RT=1.71 min.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1nccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2ccnc(Br)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
To a stirred solution of 7-bromo-1H-pyrrolo[2,3-c]pyridine (0.2 g, 1.02 mmol) in DMF (5 mL), cooled to 0° C., was added sodium hydride (46.7 mg, 1.17 mmol). After 10 min the mixture was warmed to 25° C. After 20 min the mixture was recooled to 0° C. and (2-(chloromethoxy)ethyl)trimethylsilane (186 mg, 1.12 mmol) added drop-wise. After 5 min the mixture was warmed to 25° C. After 20 min the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water then concentrated in vacuo. Purification by chromatography (silica, 12 g Analogix column, 0-8% ethyl acetate in hexanes) gave 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (0.28 g, 84%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[O:4]1.[C:17](Cl)([CH3:19])=[O:18]>C(Cl)Cl.CCOC(C)=O>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:16])([CH3:2])[O:4][B:5]([C:10]2[CH2:11][CH2:12][N:13]([C:17](=[O:18])[CH3:19])[CH2:14][CH:15]=2)[O:6]1
Reactant: CC(=O)Cl
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (Intermediate G3, 1.4 g, 5.70 mmol) was suspended in DCM (15 mL) at 0° C., then TEA (2.384 ml, 17.10 mmol) and AcCl (0.405 ml, 5.70 mmol) were added The reaction was allowed to warm up to rt and stirred for further 30 min, then the reaction volume was reduced to 1/3 of the initial volume and the residue diluted with AcOEt (150 ml). Organic phase was washed twice with water, once with 0.2 M HClaqueous and once with saturated NaClaqueous, anhydrified over Na2SO4 and solvent removed under reduced pressure to give the title compound (1.24 g, 87% yield) as yellowish solid.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH:8]([C:14]2([O:19][CH2:18][CH2:17][O:16]2)[CH3:15])[C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[NH4+].[OH-].Cl.[C:25]1(=O)OCC[CH2:26]1>>[CH2:25]([C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:21][CH:20]=1)([C:14]1([O:16][CH2:17][CH2:18][O:19]1)[CH3:15])[C:9]([OH:11])=[O:10])[CH3:26]
Reactant: C=Cc1ccc(CC(C(=O)OCC)C2(C)OCCO2)cc1
Reactant: O=C1CCCO1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: C=Cc1ccc(CC(CC)(C(=O)O)C2(C)OCCO2)cc1
Temperature: 110 °C

Procedure:
Ethyl 2-(4-vinylbenzyl)-3,3-(ethylenedioxy)butanoate polymer (formed in Example 3) (1.9 g, 7.7 mmol) was dissolved in g-butyrolactone (30 ml). A solution of NH4OH (30% in water) was added and the solution warmed to 110 ° C. for 5 hours. The resultant solution was made slightly acidic with the addition of HCl and the ethyl 2-(4-vinylbenzyl)-3,3-(ethylenedioxy)butanoic acid polymer precipitated into toluene and dried as a white powder (0.6g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[C:4]([CH3:32])[CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[C:4]([CH3:32])[CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3C)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1C)c1c[nH]c2c(CSC)cc(F)cc12
Yield: 31.5 %

Procedure:
2.1 mg (34 μmol) of copper powder were added to a solution of 2.48 g of the compound from Example 92A in 28 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) to result in 0.69 g of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]([NH:15][S:25]([C:18]3[C:19]([CH3:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=3[Cl:16])(=[O:27])=[O:26])[S:13][CH:14]=2)=[CH:2]1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1nc(-c2csc3ccccc23)cs1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2csc3ccccc23)cs1

Procedure:
The title compound was prepared from 4-(1-benzothien-3-yl)-1,3-thiazol-2-amine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (47.0 mg) with purity >90%. MS (pos) m/z 455.0, 457.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH:32]([OH:34])[CH3:33])[C:4]1[N:5]=[N:6][C:7]([NH:10][NH:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:9]=1)[CH3:2].[ClH:35]>C(O)C>[ClH:35].[ClH:35].[CH2:1]([N:3]([CH2:31][CH:32]([OH:34])[CH3:33])[C:4]1[N:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCN(CC(C)O)c1ccc(NNC(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Agent: Cl
Solvent: CCO
Product: CCN(CC(C)O)c1ccc(NN)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 50% suspension of 1.5 g sodium hydride in 100 ml tetrahydrofuran, 3 g ethyl-(2-hydroxypropyl)amine are added; this is stirred at room temperature for 30 minutes, thereafter 4.5 g of 3-chloro-6-triphenylmethylazopyridazine are added. Stirring is maintained for 5 minutes, the organic phase is washed with a saturated solution of sodium chloride, rendered anhydrous and evaporated to dryness under a vacuum. The residue is taken up with ethyl alcohol, diluted with water, and the precipitate is collected under a vacuum which is then triturated with diisopropyl ether to yield 4 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-triphenylmethylazopyridazine melting at 137° C. (with decomposition). A solution of 3 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-triphenylmethylazopyridazine in 300 ml ethyl alcohol and 50 ml tetrahydrofuran containing 300 mg 5% palladium on carbon is hydrogenated at room temperature and pressure. The catalyst is filtered out, then the residue is evaporated and triturated with diethyl ether to yield 2.5 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-(2-triphenylmethylhydrazino)pyridazine melting at 122° C. (with decomposition). A solution of 2 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-(2-triphenylmethylhydrazino)pyridazine in 100 ml absolute ethyl alcohol is mixed with 2.5 ml concentrated hydrochloric acid and stirred for 15 minutes at room temperature. This is evaporated under a vacuum and the residue taken up with isopropyl alcohol. This is diluted with diisopropyl ether to yield 1.2 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-hydrazinopyridazine dihydrochloride melting at 208°-212° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])([CH3:14])[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@@]1(O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Product: CC1(C)CNCC=C1c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 98 %

Procedure:
A suspension of (R)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol, D-(−)-Tartaric Acid (6.2 g, 15.90 mmol) in concentrated hydrochloric acid (150 mL) was refluxed for 27 hours, during which time a clear solution was observed. The solution was cooled to 0° C., which caused a white solid to precipitate, and the pH was adjusted to ˜13 with the slow, careful addition of solid sodium hydroxide. The aqueous was extracted with EtOAc (3×300 mL), the combined organic layers were washed with 1N NaOH (3×100 mL), once with brine (100 mL), then dried over sodium sulfate and concentrated in-vacuo to yield the title compound (3.46 g, 15.60 mmol, 98% yield) as a pale yellow oil. MS (ESI+)=222/224, (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:3][C:4]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-n3cccn3)cc(Br)c2s1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-n3cccn3)cc(-c3cccnc3)c2s1
Temperature: 120 °C
Yield: 24.5 %

Procedure:
To a solution of 1-(7-bromo-5-pyrazol-1-yl-benzothiazol-2-yl)-3-ethyl-urea (0.27 g, 0.74 mmol) in DMF: H2O (2:1, 15 mL) was added 3-pyridyl boronic acid (0.11 g, 0.88 mmol) and K3PO4 (0.17 g, 0.81 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.077 g, 0.11 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 2 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (230-400 M) using EtOAc-Hexane (70:30) to provide the title compound (0.066 g, 22%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[O:19][C:18]1([CH2:25][CH2:24][CH2:23]1)[C:14]1([CH2:17][O:16][CH2:15]1)[C:13]2=[O:26].CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.[Cu]I>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([C:10]2[CH:11]=[C:12]3[C:20](=[CH:21][CH:22]=2)[O:19][C:18]2([CH2:25][CH2:24][CH2:23]2)[C:14]2([CH2:17][O:16][CH2:15]2)[C:13]3=[O:26])[CH:8]=1
Reactant: COCc1cn[nH]c1
Reactant: O=C1c2cc(Br)ccc2OC2(CCC2)C12COC2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COCc1cnn(-c2ccc3c(c2)C(=O)C2(COC2)C2(CCC2)O3)c1
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A mixture of 4-(methoxymethyl)-1H-pyrazole (145 mg, 1.29 mmol), 6′-bromo-4′H-dispiro[cyclobutane-1,2′-chromene-3′,3″-oxetan]-4′-one (200 mg, 0.647 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (74 mg, 0.52 mmol) and K2CO3 (268 mg, 1.94 mmol) in NMP (2 mL) was purged with argon. To the mixture was added CuI (49 mg, 0.26 mmol), and the mixture was sealed and stirred for 1 hour at 150° C. and 0.5 hours at 170° C. under a microwave irradiation. The mixture was partitioned between EtOAc and saturated aqueous NH4Cl. The organic layer was washed with water (two times) and brine, dried over MgSO4, filtered, and the filtrate was evaporated. Silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 45%) afforded 6′-[4-(methoxymethyl)-1H-pyrazol-1-yl]-4′H-dispiro[cyclobutane-1,2′-chromene-3′,3″-oxetan]-4′-one (97 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[O:5])C.[OH-].[Li+].Cl>C1COCC1.O>[CH3:16][O:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.5 %

Procedure:
6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1H-indole-2-carboxylic acid (4.60 g). This material (4.64 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g) in dichloromethane (200 mL) were treated with N-methylpiperazine (3.23 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2 M ammonia in methanol/dichloromethane) to give (6-Methoxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 mL). At room temperature, 1 M boron tribromide (1.5 mL) was added dropwise. The reaction mixture was heated to reflux overnight, and then cooled, quenched with saturated sodium hydrogencarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (0-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.12 g). 1H NMR (400 MHz, CDCl3/CD3OD): δ 7.22 (d, J=8.41 Hz, 1H), 6.62 (d, J=2.15 Hz, 1H), 6.5′-6.47 (m, 2H), 3.69 (br s, 4H), 2.30 (t, J=5.09 Hz, 4H), 2.13 (s, 3H). MS (electrospray): exact mass calculated for C14H17N3O2, 259.13; m/z found, 260.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4].C(NC(C)C)(C)C.[N:23]1([C:29]2[N:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:31]([C:30]1[C:29]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=3)=[O:4])[CH2:27][CH2:28]2)=[N:36][CH:35]=[CH:34][CH:33]=1)#[N:32]
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: O=C(CCl)Nc1ccc(C(F)(F)F)cc1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: N#Cc1cccnc1N1CCN(CC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
2-Chloro-N-(4-trifluoromethylphenyl)acetamide (820 mg, 3.45 mmol, Maybridge) and N,N-diisopropylamine (2.5 mL) in toluene (50 mL) were treated with 2-piperazin-1-ylnicotinonitrile (800 mg, 4.25 mmol, Chess) and heated to 60° C. for 18 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution with 20% to 40% ethyl acetate:hexanes) to provide 1.05 g (78% yield) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.69 (m, 4H), 3.26 (s, 2H), 3.68 (m, 4H), 6.93 (dd, 1H, J=7.5, 4.7 Hz), 7.68 (AA′BB′, 2H, J=8.8 Hz), 7.88 (AA′BB′, 2H, J=8.5 Hz), 8.07 (dd, 1H, J=7.8, 2.0 Hz), 8.42 (dd, 1H, J=4.7, 2.0 Hz), 10.14 (br s, 1H); MS (DCI/NH3) m/e 390 (M+H)+;
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[CH3:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[CH3:18])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC(Cl)(Cl)COc1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC(C)(Cl)Cl)ncn1
Reaction time: 0.17 h
Yield: 39 %

Procedure:
In 1.5 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.07 g of 2-butyn-1-ol was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 0.18 g of 4-chloro-6-(2,2-dichloropropyloxy)pyrimidine in tetrahydrofuran, followed by stirring for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.08 g of 4-(2-butynyloxy)-6-(2,2-dichloropropyloxy)pyrimidine (the present compound (37)).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(Cl)(Cl)Cl.[CH3:23][O:24][C:25]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH:12][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:25]=3[O:24][CH3:23])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccc3c(c2[N+](=O)[O-])C(=O)NC(=O)C3(C)C)c(OC)c1

Procedure:
2.7 gm of 4,4-dimethyl-7-amino-8-nitro-2H,4H-isoquinoline-1,3-dione were admixed with 50 ml of chloroform and 2.5 ml of triethylamine. Subsequently, 2.2 gm of 2,4-dimethoxybenzoylchloride were added, and the mixture was refluxed for 2 hours. After cooling the solution was evaporated and the precipitate was suction-filtered off and digested with water while heating.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: CCc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1
Yield: 90 %

Procedure:
The title compound was prepared in 90% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-ethylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H16N4, 289. Found, 289.