Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.[N:20]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[N+:17]([C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][N:20]=[C:4]2[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)([O-:19])=[O:18]
Reactant: O=N[O-]
Reactant: CN1CCC(C(=O)c2cc([N+](=O)[O-])ccc2N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: -3 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a −5° C. solution of 4-(2-amino-5-nitrobenzoyl)-1-methylpiperidine (570 mg, 2.2 mmol) in 9.6N aqueous hydrochloric acid (10 mL) was added dropwise a solution of sodium nitrite (164 mg, 2.4 mmol) in water (3 mL). This resulting diazonium salt solution was stirred 10 minutes at −5° C. then added dropwise to a −5° C. solution of stannous chloride dihydrate (1.95 g, 8.6 mmol) in 12N aqueous hydrochloric acid (6 mL). The resulting solution was stirred 2 hours at −3° C., basified with 1N aqueous sodium hydroxide (190 mL) and extracted exhaustively with ethyl acetate and methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 420 mg of a brown residue. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 177 mg (31.4%) of the title compound. The product was crystallized as the hydrochloride salt. EA calculated for C13H17ClN4O2: C, 52.62; H, 5.77; N, 18.88. Found: C, 52.39; H, 5.96; N, 18.77.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@@H:3]([N:5]([CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13])[C:6](=[O:9])[O:7][CH3:8])[CH3:4].[Br-].[CH2:24]1[CH2:28]OC[CH2:25]1>>[CH3:22][C:2]([CH3:21])([CH3:1])[C@@H:3]([N:5]([CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([OH:13])[CH2:28][CH:24]=[CH2:25])[C:6](=[O:9])[O:7][CH3:8])[CH3:4]
Reactant: C1CCOC1
Reactant: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)C(C)(C)C
Agent: [Br-]
Product: C=CCC(O)(CCN(C(=O)OC)[C@@H](C)C(C)(C)C)c1ccc(F)cc1
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (S)-methyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (4.5 g, 0.015 mol) in THF (60 mL) was added allymagnesium bromide (1 M, 30 mL, 0.03 mol) dropwise at −78° C. under N2. After adding completely, the reaction mixture was stirred at it overnight. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give methyl (S)-3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-hydroxyhex-5-enyl)carbamate (4.80 g, 92%), which was used for the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([F:19])[C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.C(N(CC)CC)C.[O:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([F:19])[C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: O=c1[nH]c2c(F)cc(Cl)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(F)cc(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride D9 (0.36 mmol, 0.1 g) was dissolved in dichloromethane (10 ml) and triethylamine (3 eq., 1.08 mmol, 80 microliters), tetrahydro-4H-pyran-4-one (4.5 eq., 1.62 mmol, 162 mg), sodium triacetoxyborohydride (4.5 eq., 1.62 mmol, 345 mg) were added at room temperature and the mixture was stirred at room temperature for 2 hours. Additional tetrahydro-4H-pyran-4-one (2 eq., 0.72 mmol, 72 microliters) and sodium triacetoxyborohydride (2 eq., 0.72 mmol, 0.015 g) were added at room temperature and the mixture was stirred at room temperature for two further hours. The mixture was quenched with water and brought to pH 10 by sodium hydroxide (aqueous solution). The organic phase was separated from the aqueous phase (by hydrophobic filters) and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 6-chloro-4-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 15 mg, 11%, M++H=354 and 356, which was converted to the hydrochloride salt using 1M HCl in diethyl ether.
Reaction SMILES: [C:1]1(=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3](=[O:11])[CH2:2]1.C(N(CC)CC)C.C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(O)C>[N+:29](=[C:2]1[C:3](=[O:11])[CH2:4][C@H:5]2[C@@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[C:1]1=[O:12])=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1CC(=O)C2CCCCC2C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)C[C@@H]2CCCC[C@H]2C1=O
Temperature: 0 °C

Procedure:
A solution of 1.06 gm (6.38 nmole) of decalin-1,3-dione in 3 mL of dry ethanol was cooled in an ice bath and treated with 0.89 mL of (6.4 mmole) triethylamine followed by 1.128 gm (6.50 mmole) of p-toluenesulfonyl azide. The mixture was stirred in the ice bath for 4 hours, then concentrated in vacuo (less than 40° C.). The residue was dissolved in 45 mL of ether and the ether washed with a solution of 0.42 gm KOH in 30 mL of water, dried (Na2SO4), filtered, and concentrated to 1.22 gm of an orange oil. This was chromatographed on 40-micron silica giving 0.45 gm of trans-2-diazodecalin-1,3-dione, mp 81°-3° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:34])=[O:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 27 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.102 mmol) obtained in Example 1, (3), and phenylmethanesulfonyl chloride (29 mg, 0.150 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (13 mg, yield 27%) as slightly brown amorphous.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10](C)([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[N:26](C3CO3)[CH:27]=[CH:28][C:5]=21.[O:32]1[CH2:34][CH:33]1[CH2:35]N1C2C(=C(O)C=CC=2)C=C1.BrC1C(OC)=C(OC)C=C(C=1)C=O.C(#N)CC#N.N1CCCCC1>>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[N:26]([CH2:35][CH:33]3[CH2:34][O:32]3)[CH:27]=[CH:28][C:5]=21
Reactant: COc1cc(C2(C)C(C#N)=C(N)Oc3c2ccc2c3ccn2C2CO2)cc(Br)c1OC
Reactant: Oc1cccc2c1ccn2CC1CO1
Agent: COc1cc(C=O)cc(Br)c1OC
Solvent: C1CCNCC1
Solvent: N#CCC#N
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2CC2CO2)cc(Br)c1OC

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-oxiranyl-methyl-4H-pyrrolo[2,3-h]chromene: The title compound was prepared from 1-oxiranylmethyl-4-hydroxy-indole (70 mg, 0.37 mmol), 5-bromoveratraldehyde (91 mg, 0.37 mmol), malononitrile (25 mg, 0.37 mmol) and piperidine (0.01 mL, 0.18 mmol), similar to Example 16, to yield 80 mg (45%) of a white solid. 1H NMR (CDCl3): 7.15 (dd, J=1.5 Hz, 1H), 7.10 (dd, J=2.7 Hz, 1H), 6.92-6.91 (m, 1H), 6.78-6.75 (m, 2H), 6.62 (dd, J=0.9 Hz, 1H), 4.77 (s, 1H), 4.70 (brs, 2H), 4.48-4.43 (m, 1H), 4.15-4.13 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.28-3.27 (m, 1H), 2.84-2.81 (m, 1H), 2.48-2.44 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>>[OH:1][C:2]1[CH:11]=[C:10]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Yield: 85.5 %

Procedure:
Following the basic procedure of Example 1(a), by reacting 34 g (122 mmol) of methyl 2-hydroxy-4-iodobenzoate with 34 ml (244 mmol) of trimethylsilylacetylene, 25.9 g (85%) of the expected compound were obtained in the form of a brown oil.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.Br[C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[O:29][CH2:30][CH:31]([OH:40])[CH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>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.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:43]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][CH:31]([OH:40])[CH2:32][CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[CH:41][CH:42]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: OC(CCc1cccnc1)COc1cccc(Br)c1
Reactant: COc1cccc(B(O)O)c1
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: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1
Temperature: 120 °C

Procedure:
Prepared according to the method as described in Example 33a) from toluene (8 ml), aqueous sodium carbonate (2 M, 2.47 ml), 3-methoxybenzeneboronic acid (0.413 g), ethanol (2 ml), (±)-1-(3-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.79 g, Example 56a) and tetrakis(triphenylphosphine)palladium(0) (0.071 g) with heating at 120° C. for 4 hours. After work up the residue was purified by column chromatography over silica with ethyl acetate to give the title compound as a white solid after trituration with ether:hexane (0.27 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].C1(=[O:20])CCCCC1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:1][C:2]1[C:7]([C:8]([OH:20])=[O:9])=[C:6]([CH3:10])[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[CH3:13]
Reactant: Cc1c(C)c(C)c(C=O)c(C)c1C
Reactant: O=C1CCCCC1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1c(C)c(C)c(C(=O)O)c(C)c1C
Yield: 78.8 %

Procedure:
To a flask equipped with a stirrer, oxygen inlet and condenser were added pentamethylbenzaldehyde (12.0 g, 68 mmol), 40 mL (0.387 mol) of cyclohexanone and 6 mg of cobalt (II) acetate dissolved in several drops of acetic acid. Oxygen was bubbled in while the solution was stirred rapidly and heated at 50° for 4 hours. The solution was mixed with 100 mL of cyclohexane and the mixture was extracted with 100 mL of 6% aqueous sodium bicarbonate solution. The aqueous layer was separated and the organic layer was washed with 50 mL of water. The combined aqueous layers were acidified with concentrated hydrochloric acid. The white crystalline solid product was collected by filtration, washed with water and air dried. A total of 10.3 g (78% yield) of pentamethylbenzoic acid was obtained: mp 202°-206°.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9].S(Cl)([Cl:15])=O>C(OCC)C.CN(C)C=O>[Cl:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9]
Reactant: O=S(Cl)Cl
Reactant: N#CCOc1cccc(CO)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CCOc1cccc(CCl)c1

Procedure:
α-(3-Hydroxymethylphenoxy)acetonitrile (0.055 mol) in diethylether (150 ml) is stirred with thionyl chloride (0.060 mol) and a few drops of dimethylformamide at 40° C. for 1 hr. the solution is washed with water and brine, then evaporated to give α-(3-chloromethylphenoxy)acetonitrile as a yellow oil which is used directly in the next step.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22](O)=[O:23])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:35]>C1(C)C=CC=CC=1.CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([NH2:35])=[O:23])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1OC1CCCC1
Reactant: CC#N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCN(C(=O)C(N)=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a magnetically-stirred suspension of 2-[4-(3-cyclopentyloxy-4-methoxyphenyl) piperidin-1-yl]-2-oxo-acetic acid (2.5 mmol, 0.868 g) in dry toluene (25 mL) at room temperature was added oxalyl chloride (2.0M solution in CH2Cl2 ; 2.75 mmol, 1.38 mL) dropwise over 10 minutes, followed by DMF (4 drops). The resulting homogenous solution was stirred at room temperature for 30 minutes, after which time saturated NH3 /CH3CN (25 mL) was added dropwise over 30 minutes. A white solid precipitated out of solution, and the heterogeneous mixture was stirred for 1 hour at room temperature. The solution was diluted with H2O to dissolve the white precipitate and the volatiles were removed in vacuo. The solid was partitioned between saturated NaHCO3 (150 mL) and EtOAc (150 mL) and the aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were washed with H2O (300 mL), dried (Na2SO4) and concentrated in vacuo to yield the title compound as a white foam, mp=66°-66.5° C. (1.8 mmol, 0.640 g, 74% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18].S(Cl)(Cl)=O>CO>[CH:10]([C:9]1[C:8]([OH:13])=[C:7]([CH:14]([CH3:15])[CH3:16])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:12]=1)([C:9]1[C:8]([OH:13])=[C:7]([CH:14]([CH3:16])[CH3:15])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:12]=1)[C:25]1[C:24]([OH:27])=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:26]=1
Reactant: CC(C)c1cc(C(C)(C)C)cc(C=O)c1O
Reactant: CC(C)c1cc(C(C)(C)C)ccc1O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(C)c1cc(C(C)(C)C)cc(C(c2cc(C(C)(C)C)cc(C(C)C)c2O)c2cc(C(C)(C)C)cc(C(C)C)c2O)c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Compound 3 was synthesized as described elsewhere with minor modifications.6 Briefly, a sample of 5-(tert-butyl)-2-hydroxy-3-isopropylbenzaldehyde (2) (5.08 g, 24.3 mmol) was combined with 2 equivalents of 4-(tert-butyl)-2-isopropylphenol (1) (9.17 g, 47.7 mmol) and 14 mL of methanol in a 100 mL schlenk flask. With a sodium carbonate trap connected to the reaction flask, the reaction mixture was cooled to 0° C. and thionyl chloride (11.4 mL, 157.7 mmol) was added dropwise causing an immediate change from orange/yellow to dark purple for the reaction mixture. The reaction was stirred overnight. The precipitate that was formed was collected by filtration. The residue was recrystallized from hexanes to afford 3 as a pale purple solid (6.88 g) in 48% yield with respect to the starting salicylaldehyde. 1H NMR (CDCl3-d) δ ppm 1.20 (27 H, s), 1.26 (18 H, d, J=6.9 Hz), 3.22 (3 H, spt, J=6.9 Hz), 4.91 (3 H, s), 5.83 (1 H, s), 6.81 (3 H, d, J=2.3 Hz), 7.18 (3 H, d, J=2.3 Hz). 13C-{1H} NMR, δ 22.7, 27.5, 31.4, 34.3, 41.8, 122.2, 123.7, 125.7, 135.0, 143.5, 148.9. Anal. calcd. for C40H58O3: C, 81.86; H, 9.96; N, 0.00. Found: C, 81.79; H, 10.32; N, 0.00.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[CH2:4][C:5]#[N:6].[CH2:13]([N:20]=[N+:21]=[N-:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>O1CCCC1.O>[C:14]1([CH2:13][N:20]2[C:5]([NH2:6])=[C:4]([C:3]3[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=3[CH3:1])[N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2nnn(Cc3ccccc3)c2N)c(C)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.8 %

Procedure:
A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. Solvent was removed in vacuo to give a brown oil. Trituration with ether and filtration afforded a yellow solid (1.12 g, 61% yield): NMR (CDCl3,300 MHz):7.60–7.30 (m, 5H), 7.30–7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M+H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:29])=[CH2:28])[C:19]=4[S:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Zn](CC)[CH2:31]C.ClCI>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5([CH3:31])[CH2:29][CH2:28]5)[C:19]=4[S:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC[Zn]CC
Reactant: C=C(C)c1cccc2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)sc12
Agent: ClCI
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4c(C5(C)CC5)cccc34)c(C)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A solution of 8-(1-ethyl-propyl)-3-(7-isopropenyl-2-methyl-benzo[b]thiophen-3-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (97 mg, 0.24 mmol) in CH2Cl2 (5 mL) is cooled to 0° C., treated with 1.0 M Et2Zn (1.2 mL, 1.2 mmol) and ClCH2I (176 μL, 2.4 mmol). The reaction is stirred at 0° C. for 30 min, then at RT for 1 h. The reaction is cooled to 0° C., quenched with sat. NH4Cl (10 mL); diluted with H2O (15 mL); extracted with EtOAc (3×30 mL); dried with Na2SO4, filtered and concentrated. The crude material is subjected to the same condition to ensure the conversion is completed. Purification of the crude material using silica gel chromatography gives the title compound (12.4 mg, 0.03 mmol, 12%). 1H NMR (CDCl3): δ 0.80-0.84 (m, 2H), 0.92 (t, J=6.9 Hz, 6H), 0.97-1.11 (m, 2H), 1.51 (s, 3H), 1.79-1.94 (m, 4H), 2.41 (s, 3H), 2.43 (s, 3H), 2.46 (s, 3H), 3.22-3.54 (m, 1H), 6.69 (s, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H) ppm. ES-MS (m/z): calcd for C26H31N3S (M+H)+: 418.6. found: 418.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][C:9]2[C:14]3[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[CH3:2].[OH:29][CH2:30][CH2:31][NH2:32]>>[CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][C:9]2[C:14]3[N:15]=[C:16]([NH:32][CH2:31][CH2:30][OH:29])[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: NCCO
Reactant: CCOc1ccc(Nc2ncnc3c(N4CCS(=O)CC4)nc(Cl)nc23)cc1
Product: CCOc1ccc(Nc2ncnc3c(N4CCS(=O)CC4)nc(NCCO)nc23)cc1

Procedure:
This compound was prepared analogous to Example 3 from 8-(4-ethoxy-anilino)-2-chloro-4-(1-oxido-thiomorpholino) pyrimido[5,4-d]pyrimidine (melting point: 237°-240° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([C:11]([F:14])([F:13])[F:12])=[N:5]1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:9][C:8]1[N:4]([CH2:3][CH2:2][O:1][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[N:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7]=1[OH:10]
Reactant: Cc1c(O)c(C(F)(F)F)nn1CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(O)c(C(F)(F)F)nn1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of 1-(2-hydroxyethyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ol (600 mg, 2.86 mmol; Kenkyu Hokoku—Asahi Garasu Kogyo Gijutsu Shoreikai, 1988, 51, 139–49) in dichloromethane (10 ml) and ethyl acetate (4 ml) was added para-toluenesulphonic acid (27 mg, 0.14 mmol) followed by 3,4-dihydro-2H-pyran (340 μl, 3.7 mmol). The reaction mixture was stirred at room temperature for 3 hours before being concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (60:40, by volume) to provide the title compound (560 mg) as white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH3:41])[CH:44]=3)(=[O:51])=[O:50])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2Cl)c1
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran (5 mL), 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) under ice-cooling and the mixture was stirred for 45 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 501 mg, 98%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[OH-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
4-Methoxyacetophenone (1.4 g) and sodium hydroxide (0.2 g) were suspended in 15 Ml of methanol pre-chilled at −10° C. The solution was kept for 1 hr under 0° C. with stirring. Benzaldehyde (1 g) was added thereto, and refluxed for 10 hr at room temperature with stirring. After neutralization with 5% hydrochloric acid solution, the product was extracted with 100 Ml of ethylacetate. The extracted organic phase was dried with anhydrous magnesium sulfate, and evaporated under vacuum. The resulting 1.3 g of white powder was purified through silica gel column chromatography (5×3 cm, Merk), which is eluted with n-hexane:ethylacetate (v/v, 1:7). The purified compound was identified as follows: