Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@@H:27]([C:32](O)=[O:33])[C@@H:28]([CH2:30][CH3:31])[CH3:29])=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:16])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([C@H:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36].O.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:35]([C@H:37]([NH:44][C:32](=[O:33])[C@@H:27]([C@@H:28]([CH2:30][CH3:31])[CH3:29])[NH:26][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36]
Reactant: CC[C@H](N)c1ccccc1
Reactant: CC[C@@H](C)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)[C@H](C)CC)c1ccccc1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a solution of 6.69 g (14.2 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine and 2.04 g (15.1 mmols) of (S)-α-ethylbenzylamine in 200 ml of methylene chloride were added 2.73 g (14.2 mmols) of water-soluble carbodiimide hydrochloride and 1.92 g (14.2 mmols) of HOBt under cooling and stirred for one hour under cooling and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and 150 ml of ethyl acetate was added. The resulting residue was washed two times each with 70 ml of aqueous 5% citric acid, once with 70 ml of water, two times each with 70 ml of aqueous 5% sodium hydrogencarbonate and once with 70 ml of brine in that order. The resulting organic layer was dried with anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was dissolved in chloroform and concentrated under reduced pressure. The resulting solid residue was washed with ethyl acetate and dried to obtain 2.81 g (4.7 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine (S)-α-ethylbenzylamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:12])[CH2:9][C:10]#[N:11].F[C:14]1C=CC=CC=1C(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:12])([CH3:14])[CH2:9][C:10]#[N:11]
Reactant: CC(=O)c1ccccc1F
Reactant: N#CCC(O)c1ccccc1F
Product: CC(O)(CC#N)c1ccccc1F

Procedure:
3-(2-Fluoro-phenyl)-3-hydroxy-butyronitrile was prepared by the same procedure of 3-(2-fluoro-phenyl)-3-hydroxy-propionitrile from 1-(2-fluoro-phenyl)-ethanone in example 6.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Cl.CO.[NH3:16].[CH3:17][S:18]([OH:21])(=[O:20])=[O:19]>CO>[CH3:17][S:18]([OH:21])(=[O:20])=[O:19].[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)(=[NH:16])[NH2:2]
Reactant: N
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CO
Product: N=C(N)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
2-Cyano-6-hydroxybenzothiazole, (White, E. H.; McCapra, F.; Field, G. F. The structures and synthesis of firefly luciferin. J. Am. Chem. Soc. 1963, 85, 337-342; 0.8 g, 4.54 mmol) was added to a cooled, saturated methanol-HCl solution (15 mL) and the mixture was stirred for 24 h at ambient temperature. The reaction mixture was concentrated in vacuo to give a solid. The solid was suspended in anhydrous methanol (40 mL) and gaseous NH3 was introduced into the mixture at ambient temperature for 1 h and then at 50° C. for 2 h to give a homogenous solution. The solvent was evaporated in vacuo, and the resulting brown solid was suspended in methanol (15 mL) and then treated with a saturated solution of NaHCO3 (50 mL). The precipitate was collected by filtration, washed with water (2×10 mL) and then dried in open air for 3 h. The solid (0.94 g) was suspended in 3 mL of methanol and then treated with methanesulfonic acid (0.45 g, 4.69 mmol). The precipitated material was recrystallized from methanol to give 0.75 g (57%) of 2-amidino-6-hydroxybenzothiazole methanesulfonate as a yellow solid, mp 276-278° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.IC.O.[C:25](=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH3:25]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c2c(c(=O)n1-c1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 98 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 1.06 g, 3.7 mmol) and iodomethane (450 μL, 7.2 mmol) in N,N-dimethylformamide (20 mL) in a sealed tube was heated to 98° C. and stirred for 5 h. The reaction mixture was allowed to cool and water (20 mL) and saturated sodium bicarbonate solution (200 mL) were added. The solution was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine (200 mL), dried (sodium sulfate), filtered, and evaporated. The residue was triturated with hexanes (4×5 mL) and the solid was recrystallized twice from ethyl acetate/hexanes to give (4S,7R)-2-(2-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (451 mg, 41%) as white needles. ES(+)-MS (M+H) 301.
Reaction SMILES: S(Cl)(Cl)=O.C1C2C(C(O)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:21]1[C:33]2[CH:32]([C:34]([NH2:36])=O)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.P(Cl)(Cl)(Cl)=O>>[C:34]([CH:32]1[C:33]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)#[N:36]
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Agent: O=C(O)C1c2ccccc2-c2ccccc21
Solvent: O=S(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1c2ccccc2-c2ccccc21
Yield: 65 %

Procedure:
100 ml (1.37 mol) of thionyl chloride are added to 21.0 g (0.10 mol) of fluorene-9-carboxylic acid and the mixture is refluxed for about 90 minutes. The excess thionyl chloride is evaporated off on a vacuum rotary evaporator. The residue is taken up three times with about 50 ml of toluene each time and the mixture evaporated on a vacuum rotary evaporator. The oily residue is added in portions to a mixture of about 1 kg of ice and 240 ml of concentrated ammonia solution. The fluorene-9-carboxylic acid amide which has precipitated is filtered off, washed with water and dried under a high vacuum. The dried fluorene-9-carboxylic acid amide is then added to 160 ml (1.75 mol) of phosphorus oxychloride and the mixture is refluxed for about 2 hours. The reaction mixture is cooled and concentrated on a vacuum rotary evaporator. The residue is taken up in toluene and the mixture is washed with water. The organic phases are combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallization of the residue from cyclohexane gives 12.4 g (65%) of 9-cyano-fluorene, melting point 152°-154° C. (compound (101), Table 1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) were added 4-(2-propoxyethoxy)phenyl borate (207 mg) and potassium carbonate (234 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 97) (218 mg).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(C)[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C(O)=CC=CC=1C.C1(=O)CCCCC1>>[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:13]1(=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Oc1ccccc1
Reactant: Cc1ccccc1O
Solvent: Cc1cccc(O)c1
Solvent: O=C1CCCCC1
Product: C1=CCCCC1
Reaction time: 0.5 h

Procedure:
In this example, the reaction time was set to 0.5, 1 and 2 hours, respectively. The experimental results were described as follows. When the reaction time was 0.5 hour, the selectivity of crude phenol was 100%, wherein phenol was 60% and the rest was o-cresol and m-cresol. When the reaction time was 1 hour, the selectivity of crude phenol was about 85%, and the rest was cyclohexanone. When the reaction time was 2 hours, the selectivity of crude phenol was about 82%. In this product, cyclohexene was also obtained in addition to cyclohexanone. Therefore, the o-methoxyphenol was first formed into phenol and other phenolic compounds via a hydrocracking reaction. As the reaction time was increased, the cyclohexanone was formed by the continuous hydrogenation reaction and de-olefin. Next, the cyclohexene was further formed by hydrodeoxygenation. Thus, to this example, when the reaction time was set to 0.5 hour, the phenolic compounds with high yield were immediately obtained. However, as the reaction time was prolonged, other hydrogenated by-products were generated instead.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[CH3:11][N:12]([CH2:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[S:17][CH2:16]1)[CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH3:13][N:12]([CH2:14][CH:15]1[C:24]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)([OH:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[S:17][CH2:16]1)[CH3:11]
Reactant: CN(C)CC1CSc2ccccc2C1=O
Reactant: COc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)c3ccccc3SCC2CN(C)C)c1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
The corresponding Grignard reagent was prepared from 0.73 g magnesium turnings and 5.61 g 1-bromo-3-methoxy-benzene in 20 ml of dry tetrahydrofuran, with gentle boiling. A solution of 4.43 g (RS)-3-dimethylaminomethyl-thiochroman-4-one in 10 ml dry tetrahydrofuran was added drop-wise thereto at +5 to 10° C. The batch was subsequently stirred for 6 hours at 20° C. and was then decomposed with 10 ml of a saturated ammonium chloride solution. The batch was extracted three times with diethyl ether, and the combined extracts were washed with a saturated sodium chloride solution and dried over sodium sulphate. The crude product which remained after evaporating off the volatile constituents was purified by column chromatography using ethyl acetate as the elutant, whereupon 3.68 g (55.8% theoretical) of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.B([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[CH3:22])(O)O>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[CH3:22])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Br)ccc1N
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Product: Cc1cc(-c2ccc(C(=O)O)cc2C)ccc1N

Procedure:
The title compound was prepared from 4-bromo-2-methylaniline and 4-borono-3-methylbenzoic acid (D29) using a similar procedure to Description 1 as a brown solid (41%). This was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:14]=[C:15]=[S:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:17]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: Fc1cccc(-c2ccccc2N=C=S)c1
Solvent: CCO
Product: NC(=S)Nc1ccccc1-c1cccc(F)c1

Procedure:
Reaction of 3'-fluoro-2-biphenylylisothiocyanate (11.2 g) with ethanol (50 ml) with 28% aqueous ammonia solution (100 ml) for 24 hours at ambient temperature yielded N-(3'-fluoro-2-biphenylyl)thiourea (m.p. 157°-159° C.).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:17]2[C:18]([Cl:25])=[C:19]([Cl:24])[C:20]([OH:23])=[C:21]([Cl:22])[C:16]=2[O:15][N:14]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:23][C:20]1[C:19]([Cl:24])=[C:18]([Cl:25])[C:17]2[C:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[F:6])=[N:14][O:15][C:16]=2[C:21]=1[Cl:22])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: Oc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 12.5 g of 3-(2-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole is added 80.0 g of pyridine hydrochloride. The mixture is immersed in an oil bath at 200° C. for thirty minutes with stirring. The melt is poured into one liter of iced-hydrochloric acid solution, stirred for thirty minutes, and the resultant precipitate collected and dried to yield 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, mp 110° C. (dec). To 50 ml of dry dimethylformamide is added 12 g of 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, 4.4 ml of ethyl bromoacetate and 20 g of potassium carbonate. The reaction is stirred at 70° C. for 2 hrs, filtered and solvent evaporated to afford an oil, which is stirred with 500 ml water for ten minutes and then extracted with ether/ethyl acetate. The organic extract is washed with water (2X), saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate followed by recrystallization from 95% ethanol yields ethyl{[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}acetate, mp 140°-3° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cccc1Br
Temperature: -69 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
A solution of n-butyllithium (2.5M in hexanes, 2.866 L, 7.17 mol) is added dropwise to a stirred solution of diisopropylamine (745.7 g, 7.37 mol) in tetrahydrofuran (1.630 L) such that the temperature is maintained in the range −60 to −78° C. The resulting suspension is stirred for 1.5 h at −75 to −78° C. A solution of 1-bromo-3-fluorobenzene (1.228 Kg, 7.02 mol) in tetrahydrofuran (2.40 L) is added slowly to the reaction mixture over 1.5 h. Stirring is continued for 30 min at −70 to −71° C. Dimethylformamide (511.3 g) is added over 1 h. The reaction mixture is allowed to warm to −15° C. and is quenched by the slow addition of acetic acid (1.965 L) over 20 min. TBME (5.20 L) and water (6.25 L) are added. The resultant solution is stirred vigorously and the layers are separated. The aqueous layer is extracted with TBME (1.965 L) twice and the combined organic layers are washed with 0.2 M hydrochloric acid (2×5.00 L), saturated aqueous sodium hydrogen carbonate solution (2×2.50 L) and water (3.50 L). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow crystalline solid (1.367 Kg, 96%). 1H NMR (CDCl3): δ 10.36 (s, 1H), 7.49 (d, 1H, 3=7.8 Hz), 7.45-7.37 (m, 1H), 7.15 (t, 1H, J=7.9 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24]C)=[O:23].C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>C(OCC)(=O)C.O.CO.CN(C=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([OH:24])=[O:23])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(OCc3cccc(C(=O)O)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DMF (125 mL) was added to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (8.46 g, 38 mmol), methyl 3-(bromomethyl)benzoate (8.8 g, 38 mmol), and potassium carbonate (10.6 g, 77 mmol), and stirred at room temperature overnight. The resultant was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and to the resulting residue, methanol (150 mL), water (30 mL), and lithium hydroxide (4.8 g, 114 mmol) were added, and stirred at room temperature overnight. After the solvent was distilled away under reduced pressure, the resultant was diluted with ethyl acetate, then washed with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, the solid was collected by filtration.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2nnnn2C)s1
Agent: Cl
Solvent: CCO
Product: Cn1nnnc1Sc1cnc(N)s1
Yield: 48.4 %

Procedure:
A mixture of 2-acetylamino-5-(1-methyl-1H-tetrazol-5-ylthio)thiazole (2.0 g) in a mixture of ethanol (20 and aqueous 6N-hydrochloric acid (5 ml) was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was adjusted to pH 8 using aqueous sodium bicarbonate under ice cooling. The precipitates were collected by filtration, washed with water and the solid was recrystallized from ethanol to give 2-amino-5-(1-methyl -1H-tetrazol-5-ylthio)thiazole (0.81 g, yield: 48.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=2)[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]2
Reactant: COc1ccc2cc(-c3ccc(O)cc3Cl)ccc2c1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(Cl)c1

Procedure:
The title compound was prepared by reacting 3-chloro-4-(6-methoxy-2-naphthyl)phenol (2.4 g, 8.43 mmol) with boron tribromide (21.9 mL of 1.0 M solution in CH2Cl2, 21.9 mmol) according to method D to yield 2.1 g (92%) of a yellowish solid: mp 209-210° C.; 1H NMR (DMDO-d6): δ 6.86 (1H, dd, J=8.42 Hz, J=2.45 Hz), 6.97 (1H, d, 2.41 Hz), 7.11 (1H, dd, J=8.78 Hz, J=2.35 Hz), 7.16 (1H, d, J=2.15 Hz), 7.30 (1H, d, J=8.40 Hz), 7.42 (1H, dd, J=8.51 Hz, J=1.71 Hz), 7.71 (1H, d, J=8.59 Hz), 7.76 (1H, s), 7.80 (1H, d, J=8.82 Hz), 9.82 (1H, s), 10.01 (1H,s); 13C NMR (DMDO-d6): δ 108.45, 114.79, 116.21, 118.90, 125.53, 127.43, 127.77, 127.92, 129.56, 130.70, 131.73, 132.34, 133.18, 133.52, 155.56, 157.46; MS (ESI) m/z2691271 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][O:21][C:22]([CH3:28])([CH2:25][O:26][CH3:27])[C:23]#[CH:24]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:24]#[C:23][C:22]([O:21][CH3:20])([CH3:28])[CH2:25][O:26][CH3:27])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(COC)OC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(COC)OC)nc21

Procedure:
A suspension of 1.5 g (5.34 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 30 ml of a DMF/Et3N (v/v; 2/1) mixture is placed in an 80 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 1.37 g of (±)-3,4-dimethoxy-3-methylbut-1-yne (10.69 mmol), 0.101 g of CuI (0.53 mmol) and 0.187 g of bis(triphenylphosphine)palladium(II)dichloride (0.27 mmol) are successively added.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[C@H:18]1([NH2:25])[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1.C(O[Na])(C)(C)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.N#N>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CC(=O)OCC>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:24][C@H:21]4[CH2:22][CH2:23][C@H:18]([NH2:25])[CH2:19][CH2:20]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 110 °C

Procedure:
To a mixture of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (500 mg, 1.89 mmol) in toluene (10 mL) was added trans-cyclohexane-1,4-diamine (215.9 mg, 1.89 mmol), t-BuONa (302.4 mg, 3.78 mmol), BINAP (117.7 mg, 0.189 mmol), Pd2(dba)3 (173 mg, 0.189 mmol). The mixture was filled with N2 and heated at 110° C. for 4 h. TLC (PE:EA=1:1) showed the reaction was complete. The reaction was poured into water (150 mL), extracted with EA (3×50 mL). The organic layer was dried and condensed. The residue was purified by combi flash (CH2Cl2:MeOH=0˜10:1) to give trans-N1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (240 mg, yield: 37%) as a yellow solid.