Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[O:1][N:2]=2)[CH:5]=1
Reactant: C#Cc1cccc(C#N)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and the product of Example 19A (64 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 87.53 (s, 1H), 7.61 (ddd, J=8.1, 5.0, 0.8 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.88 (dt, J=7.7, 1.4 Hz, 1H), 8.23 (dt, J=8.1, 1.4 Hz, 1H), 8.31 (t, J=1.7 Hz, 1H), 8.38 (dt, J=8.1, 1.9 Hz, 1H), 8.68 (dd, J=5.1, 1.7 Hz, 1H), 9.10 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CCCOC(=O)c1cccc(CCNC)c1
Product: CCCOC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2g produced 3af. MS found M+H=481. The oxalate salt of 3af was recrystallized from ethyl acetate; mp 110-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:11][C:12]1[C:17]([O:18][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COc2cccnc2N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
A mixture of 4-methoxybenzyl bromide (25 g, 0.159 mol) and 2-amino-3-hydroxypyridine (15.9 g, 0.145 mol) in 40% aqueous sodium hydroxide solution (150 ml) and dichloromethane (150 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. The mixture was diluted with further water and dichloromethane, the product extracted into dichloromethane, and the combined organic layers washed with water, dried and evaporated. The resulting solid was washed with ether to yield the product (25.6 g, 70%)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([CH2:11][CH2:12][O:13][Si](C(C)(C)C)(C)C)[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([CH2:11][CH2:12][OH:13])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC(C#N)c1cccc(Br)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#CC(CCO)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(6-bromopyridin-2-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}butanenitrile (470 mg, 1.32 mmol) in THF (4.0 mL) was added HCl (2.0 M, 4.00 mL, 8.00 mmol). The solution was stirred at room temperature for 1 hour. It was then diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (15-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:16].O>CN(C)C(=O)C>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:19][C:18]=1[S:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)#[N:16]
Reactant: N#Cc1ccc(N)cc1Sc1ccccc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(C#N)c(Sc2ccccc2)c1)C(F)(F)F
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.62 g 10.2 mmol) in N,N-dimethylacetamide (15 mL) was rapidly added thionyl chloride (1.30 g, 10.9 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -20° C. to -5° C. for 1 hour. 4-Cyano-3-phenylthiobenzenamine (1.55 g, 6.85 mmol) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into water, extracted with ethyl ether (2×100 mL); the etheral extracts dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on 315 g of silica gel using a ethyl ether (0%, 10%, and 20%) in methylene chloride gradient. The proper fractions were combined, the solvent removed in vacuo and the residue dissolved in a mixture of 100 mL hexane and 150 mL methylene chloride. Most of the methylene chloride was distilled off as the solution was scratched to induce crystal growth. After cooling the solid was collected and dried at 85° C. /0.1 mm to yield the title propanamide (2.38 g, 91%); mp 111°-113° C. 1H--NMR (250 MHz, CDCl3): 1.67 (s, 3H, CH 3), 3.68 (s, 1H, OH), 7.27 (d, 1H, J=1.9 Hz, aromatic), 7.40-7.51 (m, 5H, aromatic), 7.59-7.69 (m, 2H, aromatic), 8.51 (s, 1H, NH). MS (CI, CH4): 367(M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1)=[CH2:19].[OH-].[K+]>CN1C(=O)CCC1>[OH:27][CH2:26][C:23]1[N:24]=[CH:25][C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:17][CH2:16][C:5]2=3)=[CH:21][CH:22]=1
Reactant: C=Cc1ccc(CO)nc1
Reactant: CN1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(C(=O)O)ccc3n2CCc2ccc(CO)nc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylic acid, (5-vinylpyridin-2-yl)methanol and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH2:15]([NH:19][C:20](=[O:32])[NH:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26]([CH:30]=1)[C:27](O)=[O:28])[CH2:16][CH2:17][CH3:18].S(Cl)(Cl)=O>ClCCl.O1CCCC1.CN(C)C=O>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:27]([C:26]3[CH:30]=[C:22]([NH:21][C:20]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])=[O:32])[CH:23]=[CH:24][C:25]=3[F:31])=[O:28])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: CCCCNC(=O)Nc1ccc(F)c(C(=O)O)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCNC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To aluminum trichloride (0.524 g, 0.00393 mol) and dichloromethane (20 mL, 0.3 mol) under an atmosphere of nitrogen was added 5-bromo-7-azaindole (67, 0.155 g, 0.000787 mol) in dichloromethane. To 5-(3-butylureido)-2-fluorobenzoic acid (588, 0.200 g, 0.000787 mol) was added 4 mL of dichloromethane (4 mL) followed by thionyl chloride (69 μL, 0.00094 mol) and a drop of N,N-dimethylformamide. After 1 hour, the reaction remained a suspension so additional thionyl chloride was added along with tetrahydrofuran. The reaction remained a suspension, so was placed in a 50° C. oil bath. After another hour, the reaction was still a suspension, and so was left to react at 50° C. overnight. The reaction had become a clear solution. All volatiles were removed under vacuum, then the residue dissolved in dichloromethane and added to the 5-bromo-7-azaindole and aluminum trichloride suspension. The reaction was allowed to stir at room temperature for 4.5 hours, followed by the addition of water and extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of methanol (0 to 10%) in dichloromethane to give the compound (P-1637, 14 mg, 4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[C:30]([O:34][C:35](=[O:43])[NH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].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>O1CCOCC1.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]>[C:30]([O:34][C:35](=[O:43])[NH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:12]=2[N:11]=[C:10]([N:7]2[C:6]4[CH:28]=[CH:29][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[N:9]=[CH:8]2)[CH:19]=[CH:18]3)[CH2:39][CH2:38]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1ccc2c(c1)ncn2-c1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C

Procedure:
Trifluoro-methanesulfonic acid 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester F (15.0 9, 35.4 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (14.2 9, 70.9 mmol) were dissolved in 200 mL of dioxane under an atmosphere of dry N2. To this solution was added Cs2CO3 (16.2 g, 49.6 mmol), racemic-BINAP (1.28 9, 2.12 mMol) and tris(dibenzylideneacetone)dipalladium (0) (1.29 9, 1.41 mMol) and the reaction mixture was heated to 100° C. and reacted at this temperature overnight. The mixture was then cooled to ambient temperature, filtered, and concentrated under vacuum to give an orange foam. The foam was chromatographed on flash silica gel eluting with a gradient from ethyl acetate (EtOAc)/DCM (1:5) to EtOAc/DCM (7:3) give 12.3 g of G as a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([F:20])[C@@H:10]2[C@H:6]1[C@@H:7]([OH:19])[CH2:8][C@H:9]2[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[O:4].C(O)(=O)C.O.Cl[O-].[Na+]>C(#N)C.CO.CC(OC)(C)C.CCCCCC.C(O)(C)C>[Si:12]([O:11][C@@H:9]1[CH2:8][C:7](=[O:19])[C@@H:6]2[C@H:10]1[C@@:5]2([F:20])[C:3]([O:2][CH3:1])=[O:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@]1(F)[C@@H]2[C@H]1[C@@H](O)C[C@H]2O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)[C@]1(F)[C@@H]2[C@H]1C(=O)C[C@H]2O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of bicyclic mono-TBS-diol 5 (2.08 kg; 6.83 mol) in acetonitrile (8.0 L) at −5° C. was added acetic acid (0.70 L) and water (2.5 L), followed by RuCl3 hydrate (14.20 g). To the mixture was added aqueous sodium hypochlorite solution (˜13%; 7.0 L) over 2 h, keeping the temperature around 0° C. The resulting mixture was stirred at 0° C. for another 1 h until all bicyclic mono-TBS-diol 5 disappeared, monitoring by TLC and NMR. The excess aqueous sodium hypochlorite was decomposed by the addition of isopropanol (0.70 L), aged at 0° C. for 15 min. The two layers were cut and the aqueous layer was discarded. The solution was used for the next reaction without further treatment. Analytical pure sample was obtained by flash silica gel column chromatography (MTBE/hexane) as colorless crystals: mp 70-71° C.; 1H NMR (400 MHz, CDCl3): δ 4.66 (d, J=5.4 Hz, 1H), 3.86 (s, 3H), 3.73 (s, 3H), 2.73 (m, 2H), 2.54 (dt, J=19.1, 5.7 Hz, 1H), 2.22 (dd, J=19.1, 3.8 Hz, 1H), 0.91 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 206.2, 167.1 (d, J=26.1 Hz), 78.9 (d, J=246.4 Hz), 67.6 (d, J=2.8 Hz), 53.4, 47.5 (d, J=3.9 Hz), 42.0 (d, J=11.4 Hz), 39.6 (d, J=13.3 Hz), 25.7, 18.0, −4.76, and −4.78; 19F NMR (376 MHz, CDCl3): δ −210.7; [α]D25=+58.2 (c 0.50, CH3OH).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](Br)[CH3:13]>CS(C)=O.O>[CH2:12]([O:11][C:5]1[C:6]([OH:10])=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[CH:8]=[O:9])[CH3:13]
Reactant: CCBr
Reactant: O=Cc1c(F)ccc(O)c1O
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccc(F)c(C=O)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To a solution of 6-fluoro-2,3-dihydroxy-benzaldehyde (1.00 g, 6.40 mmol) in dry DMSO (10 mL) was added NaOBut (1.23 g, 12.81 mmol) and ethyl bromide (0.77 g, 7.04 mmol) under N2 and stirred at RT for 18 h. The resultant mixture was diluted with water, acidified to pH ˜6 with 2N.HCl and extracted with EtOAc (4×25 mL). Combined organic layers were washed with water and brine and dried over MgSO4. Filtration and removal of the solvent under reduced pressure provided 1.05 g (5.70 mmol, 89%) of the title compound as yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.24 (s, 1H), 7.04 (dd, J=8.8, 5.3 Hz, 1H), 6.61-6.50 (m, 1H), 4.09 (q, J=7.0 Hz, 3H), 1.46 (t, J=7.0 Hz, 3H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −132.19-−132.15 (m, 1F).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.N1C=CC=CC=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(Cl)Cl.CCOC(C)=O>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:6]2[CH2:7][CH2:8][CH2:9][C@H:5]2[C:4]([O:3][CH3:2])=[O:10])(=[O:28])=[O:27])=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-proline methyl ester hydrochloride salt (2.5 g, 15.2 mmol) in DCM (20 mL) was added pyridine (2.6 mL, 33 mmol) and 4-nitrobenzenesulfonyl chloride (3.06 g, 13.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 18 h and then diluted with EtOAc (100 mL). The organic phase was washed with 1 N HCl (20 mL), brine (20 mL) and dried over MgSO4. The mixture was filtered and the solvent was removed in vacuo to give a crude yellow solid that was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:21])[CH:15]=[CH:14][C:4]=1[C:5]([CH2:7]P(=O)(OC)OC)=[O:6].[C:32]([OH:36])(=[O:35])[CH:33]=O.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:21])[CH:15]=[CH:14][C:4]=1[C:5](=[O:6])/[CH:7]=[CH:33]/[C:32]([OH:36])=[O:35]
Reactant: COc1cc(CCC(=O)Nc2nc3ccccc3s2)ccc1C(=O)CP(=O)(OC)OC
Reactant: O=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)Nc2nc3ccccc3s2)ccc1C(=O)/C=C/C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl [{2-methoxy-4-[2-(2-benzothiazolylaminocarbonyl)ethyl]benzoyl}methyl]phosphonate (6.4 g) in tetrahydrofuran (100 ml) is added 40% glyoxylic acid (7.7 ml), and further thereto is added dropwise a 5% aqueous sodium hydroxide solution (70 ml) under ice-cooling. The mixture is stirred for 30 minutes, and the mixture is acidified with 5% hydrochloric acid. The precipitated yellow powder is collected by filtration, washed with ethanol, dried, and then recrystallized from dimethylformamide-ethanol to give 2-{2-[3-methoxy-4-(trans-3-carboxyacryloyl)phenyl]ethylcarbonyl amino}benzothiazole (4.0 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C1OCCOCCOCCOCCOCCOC1.I[C:39]1[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=1>ClC1C=CC=CC=1Cl>[CH3:45][C:41]1[CH:40]=[C:39]([N:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:19]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:44]=[CH:43][CH:42]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Cc1cccc(I)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(-n2c3ccccc3c3ccccc32)c1

Procedure:
Activated Cu, (4.2 g (65.8 mmol, 1.1 eq)), 12.4 g (89.7 mmol, 1.5 eq) of K2CO3, 10 g (59.8 mmol) of carbazole, 0.47 g (3 mol %) of 18-crown-6 and 13.7 g (62.8 mmol, 1.05 eq) of 3-iodotoluene were added into 100 ml of dried 1,2-dichlorobenzene and reacted at 180° C. for 24 hours. Then, the reaction mixture was filtered to remove un-reacted Cu and salts. The filtrate was distilled under reduced pressure to remove the solvent and purified by silica gel chromatography. The product was obtained as a colorless liquid at 88.3% (15.5 g) yield. 1H-NMR (300 MHz, CDCl3): δ 8.17 (2H, d), 7.51-7.27 (10H, m), 2.51 (3H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8](Cl)[C:7](O)=[C:6](Cl)[CH:5]=1)=[O:3].[OH2:13]>>[OH:13][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: O
Product: O=C(CO)c1ccccc1

Procedure:
As a stock solution (5/5), 0.2 mM solution of 3,5-dichloro-4-hydroxyacetophenone was used. The solution was diluted with purified water to prepare 5-stage serial dilutions. To 0.02 ml of the solution in each concentration was mixed with 0.38 ml each of 0.1M citrate buffer solution (pH 5.4) containing 0.1% Triton X-100 and a buffer solution further supplemented with 0.3% BSA. Each absorbance was measured at 340 nm with a spectrophotometer to prepare the standard curve (FIG. 2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[C:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1.[CH:22]([C:24]1[C:25]([OH:38])=[CH:26][C:27]2[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=2[CH:33]=1)=[O:23].O>CN(C)C=O>[CH:22]([C:24]1[C:25]([O:38][CH2:8][C:9]#[C:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:26][C:27]2[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:34])([CH3:35])[C:32]=2[CH:33]=1)=[O:23]
Reactant: CCOC(=O)c1ccc(C#CCBr)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C#CCOc2cc3c(cc2C=O)C(C)(C)CCC3(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
0.71 g of potassium carbonate and 1.0 g of ethyl 4-(3-bromo-1-propynyl)benzoate were added to 20 ml of a solution of 0.80 g of 3-formyl-5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene in anhydrous N,N-dimethyl formamide at room temperature. The obtained mixture was stirred at 50° C. for 30 minutes, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 20% diethyl ether/n-hexane) to give 0.87 g of the title compound as a pale-yellow solid.
Reaction SMILES: [CH2:1]=[O:2].Cl.CON=C[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])[C:11]([F:27])=[CH:10][C:9]=1[Cl:28].O>C(O)(=O)C>[Cl:28][C:9]1[CH:10]=[C:11]([F:27])[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:13][C:8]=1[CH:1]=[O:2]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C=O)c(Cl)cc2F)c1=O

Procedure:
150 ml of a 30% by weight aqueous formaldehyde solution and 150 35 ml of concentrated hydrochloric acid were added dropwise to a solution of 189.9 g (0.50 mol) of 2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)benzaldehyde (O-methyl)oxime in 0.75 l of glacial acetic acid. The mixture was subsequently refluxed for two hours. After cooling, 0.75 l of water were added, whereupon the solid product of value formed was separated off and washed first with water until the reaction was neutral and then with petroleum ether. Yield: 140 g;
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[C:16](=[O:17])[O:15][CH2:14]2>ClCCl>[Br:1][CH:14]1[C:13]2[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][CH3:9])[CH:12]=2)[C:16](=[O:17])[O:15]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(Br)OC2=O

Procedure:
12 mmol of N-bromosuccinimide are added to 10 mmol of 5,6-dimethoxyphthalide dissolved in dichloromethane, and then the reaction mixture, illuminated by a halogen lamp, is heated at reflux for 2 hours. The mixture is then brought to ambient temperature and filtered, and the filtrate is subsequently evaporated, toluene is added, and the suspension obtained is filtered and the filtrate evaporated to yield the expected product.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CCCC.C(O)(=O)CCCCCCCCCCCCCCC(C)C>>[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(C)CCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Yield: 68.4 %

Procedure:
The data showing a 68.4% yield when a combination of 30% arachidic/behenic acid mixture and 70% isostearic acid is used is unexpectedly low and probably resulted from experimental error. The yield for this combination of acids is typically comparable to the yield resulting from use of oleic acid instead of isostearic acid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Nc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccccc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.