Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[CH:7]=[C:8](Br)[CH:9]=1)=[O:4].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.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>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)cn1C
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: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)cn1C
Temperature: 70 °C
Yield: 10.4 %

Procedure:
To a stirred solution of methyl-4-bromo-1-methyl-1H-pyrrole-2-carboxylate (2.5 g, 11.5 mmol) in DMF (35 mL) under argon were added sequentially Pd(PPh3)4 (0.66 g, 0.58 mmol) and phenyl boronic acid (3.46 g, 28.4 mmol). The reaction mixture was heated to 70° C., and Na2CO3 (11 g, 104 mmol) dissolved in water (30 mL) was added. The reaction mixture was heated to 110° C. (14 h), cooled to room temperature, diluted with water (250 mL), and extracted with diethyl ether (250 mL×3). The combined organic layers were dried and concentrated in vacuo. The residue was purified by silica chromatography (eluted with petroleum ether:ethyl acetate=40:1) to afford methyl-1-methyl-4-phenyl-1H-pyrrole-2-carboxylate as a white crystalline solid (0.257 g). The ester (0.26 g, 1.2 mmol) was then combined with LiOH/H2O (0.15 g, 3.6 mmol) in THF (5 mL), CH3OH (5 mL) and H2O (2.5 mL) and was stirred at 40° C. (4 h). Water (25 mL) was added and the mixture was washed with DCM (15 mL). The pH of the aqueous phase was adjusted to 5-7 using HCl (1N). The water was removed and the residue was dissolved in MeOH (100 mL) and then filtered. The filtrate was concentrated in vacuo to give 1-methyl-4-phenyl-1H-pyrrole-2-carboxylic acid as white solid. (0.419 g) 1H-NMR (CDCl3, 400 MHz): δ 4.01 (s, 3H), 7.16 (d, J=1.6 Hz, 1H), 7.23 (t, J=7.2 Hz, 1H), 7.38 (m, 3H), 7.53 (dd, J=7.2, 8.4 Hz, 2H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.[C:12]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2c(c1)OCCO2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (2.600 g; 17.10 mmol), and K2CO3 (2.598 g; 18.80 mmol) in anh. acetone (40 ml) was stirred at rt, under nitrogen, for 1 h. Iodomethane (13.340 g; 94.00 mmol) was then added, and the resulting mixture was heated at reflux, under nitrogen, for 2 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the filtrate was concentrated to dryness under reduced pressure. Et2O and water were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine as a yellow oil. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 167.11 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:11]([CH3:12])=[CH:10][C:8]([NH2:9])=[C:7]([CH3:13])[C:6]=1[Cl:14].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1.CCCCCC>[Cl:14][C:6]1[C:7]([CH3:13])=[C:8]([NH:9][C:26]([NH:25][C:23](=[O:24])[C:22]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:21]=2[F:20])=[O:27])[CH:10]=[C:11]([CH3:12])[C:5]=1[O:4][C:3]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:2]=1[CH3:1]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Cc1ccc(Oc2c(C)cc(N)c(C)c2Cl)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(Oc2c(C)cc(NC(=O)NC(=O)c3c(F)cccc3F)c(C)c2Cl)c(C)c1
Temperature: 50 °C

Procedure:
Into a solution of 4-(2,4-dimethylphenoxy)-2,5-dimethyl-3-chloroaniline (1.75 grams, 6.3 mmol) prepared in Part B in 7 milliliters of toluene, which solution was warmed to a temperature of 50° C., was added 1.14 grams (6.2 mmol) of 2,6-difluorobenzoyl isocyanate in 1.5 milliliters of toluene. The reaction mixture was heated to a temperature of 90° C. and maintained at this temperature for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with 20 milliliters of hexane and then cooled in an ice bath. A precipitate formed which was collected by filtration and washed with a cold solution of 50% hexane in toluene. After vacuum drying, a white solid (1.26 grams) which was identified as 1-[3-chloro-4-(2,4-dimethylphenoxy)-2,5-dimethylphenyl]-3-(2,6-difluorobenzoyl)urea was obtained having a melting point of 183° C.-185° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O.O.N>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cccnc12
Agent: N
Solvent: O
Product: Clc1ccnc2cccnc12

Procedure:
To 700 mg of 4-hydroxy-1,5-naphthyridine (CAS No. 5423-54-1, purchased from Specs), phosphorous oxychloride (15 ml) was added and heated to reflux for an hour. The reaction was put back to room temperature. The mixture was poured to ice, made alkaline with ammonia water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with magnesium sulfate, filtrated through NH silica gel, and the filtrate was concentrated under reduced pressure to obtain 456 mg of 4-chloro-1,5-naphthyridine (CAS No. 7689-63-6). To the obtained 4-chloro-1,5-naphthyridine (456 mg), pyridine (19 ml) and n-propylamine hydrochloride (1.32 g) were added and heated to reflux for 3.5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was partitioned between diethyl ether and 2N aqueous sodium hydroxide. The ether layer was separated and dried with magnesium sulfate. Solvent was distilled away and the residue was purified with NH silica gel (ethyl acetate/heptane system) to obtain 345 mg of the title compound (CAS No. 7689-63-6). The same operation was repeated to synthesize for another 952 mg. The structure of the obtained title compound and results from NMR measurement were as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][C:9](=O)[NH:8]2)[CH:2]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCN(c2cccnc2)N1
Product: ClC1=NN(c2cccnc2)CC1

Procedure:
3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) may also be prepared through a three step, no isolation reaction sequence as disclosed in Scheme 6. In step a2, 3-hydrazinopyridine dihydrochloride is reacted with methyl acrylate in the presence of a base such as sodium methoxide or sodium ethoxide to yield 1-(pyridin-3-yl)pyrazolidin-3-one, followed by chlorination of 1-(pyridine-3-yl)pyrazolidin-3-one with phosphoryl chloride in a two-step process to yield 3-chloro-dihydropryazole (5a). In step b2, 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) is reacted with manganese (IV) oxide to yield the product (5b). Subsequent treatment of (5b) with an acid such as hydrochloric acid may provide the salt of the product (5b). The first step may be conducted in a polar protic solvent such as methanol or ethanol, at a temperature from about 40° C. to about 80° C. The second step may be conducted in a solvent such as chlorobenzene at a temperature from about 70° C. to about 90° C. The third step may be conducted in a solvent such as chlorobenzene at a temperature from about 70° C. to about 110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH2:26][N:25]([C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:24][CH2:23][C:19]=2[N:20]=[CH:21][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Cl:33][C:32]1[C:27]([N:25]2[CH2:24][CH2:23][C:19]3[N:20]=[CH:21][N:22]=[C:17]([NH:1][C:2]4[CH:10]=[C:9]5[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]5[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=4)[C:18]=3[CH2:26]2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Clc1cccnc1N1CCc2ncnc(Cl)c2C1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CC(C)(C)c2ccc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)cc21
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A mixture of 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone (80 mg), 4-chloro-6-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (80 mg), and CH3CN (5 mL) was run in a Microwave Reactor at 180° C. for 1 h. After cooling, the mixture was treated with sat. aq. Na2CO3 and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column to give a light yellow solid (75 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.[N:14]1([C:20](=[S:22])[NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([C:20]2[S:22][CH:2]=[C:3]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)[N:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC(=S)N1CCCCC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(N3CCCCC3)n2)cc1
Yield: 77.2 %

Procedure:
4-(2-bromoacetyl)benzoic acid (1.23 mmol) and 1-piperidinethiocarboxamide (1.23 mmol) were mixed in THF (10 mL), then refluxed for 3 h. The reaction mixture was then allowed to reach room temperature and the obtained precipitate was collected by filtration and washed with 3 portions of diethyl ether. The crude product was crystallized from hot 1:1 EtOH-EtOAc to give a first harvest of colorless needles (0.28 g, 0.95 mmol). 1H NMR (DMSO-d6, 400 MHz,) δ 7.93 (4H, m), 7.40 (1H, s), 3.48 (4H, m), 1.60 (6H, m).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[N:14]=[CH:13][NH:12][C:11]2=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Yield: 41 %

Procedure:
Phosphorus oxytrichloride (0.1 ml) was added to a mixture of 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (81 mg, 0.29 mmol) and N,N-dimethylaniline (0.1 ml) in toluene (5 ml), and the mixture heated at reflux for 1 hour. The volatiles were removed by evaporation and the residue partitioned between methylene chloride and aqueous ammonia. The organic extract was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica eluting with ethyl acetate progressing through increasingly polar mixtures to methanol/methylene chloride (1/9) to give 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (40 mg, 41%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Product: Cc1ccc(-c2cc(N3CCC(C(N)=O)CC3)c3ccccc3n2)cc1

Procedure:
In a manner analogous to that of Example 1(b), but using 4-chloro-2-(4-methylphenyl)quinoline and isonipecotamide as starting materials, the named product was produced, mp. 230°-232° on recrystallization from acetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH3:14])=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:8][C:4]=2[CH:3]=1.[Br:17]Br>C(Cl)Cl>[Br:17][C:3]1[C:4]2[O:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:14])[C:5]=2[CH:15]=[CH:16][C:2]=1[OH:1]
Reactant: BrBr
Reactant: CCOC(=O)c1oc2cc(O)ccc2c1C
Solvent: ClCCl
Product: CCOC(=O)c1oc2c(Br)c(O)ccc2c1C

Procedure:
A suspension of ethyl 6-hydroxy-3-methylbenzofuran-2-carboxylate (220 mg, 1 mmole) in methylene chloride (6 ml) was treated very slowly with a solution of bromine (160 mg, 1 mmole) in methylene chloride (4 ml) and with efficient stirring.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:14][CH:15]1[C:27]2[N:26]3[CH:28]=[CH:29][N:30]=C3[C:24](=[O:31])[NH:23][C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2.C>CN(C)C=O.C(O)=O>[CH:24]([NH:23][CH:22]1[C:27]2[N:26]3[CH:28]=[CH:29][N:30]=[C:6]3[C:5](=[O:7])[NH:14][C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]1=2)=[O:31]
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=CNC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of 21.4 g of acetic anhydride and 11.5 g of formic acid is heated for 2 hours at a temperature between 50° C. and 60° C., and cooled to 20° C. 0.9 g of anhydrous sodium acetate is then added followed, after dissolution, by 2.75 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride. The mixture is stirred for 1 hour at 20° C. and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 50° C. The product obtained (4.3 g) is dissolved in 50 ml of dimethylformamide and, after addition of decolorizing charcoal, the solution is filtered. 200 ml of distilled water are then added to the filtrate and the mixture is stored for 1 hour at a temperature in the region of 5° C. The insoluble product formed is isolated by filtration, washed with 10 ml of distilled water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1.2 g of 10-formamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, melting at 280° C. (decomposition) (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 6.22 (d, J=8.5 Hz, 1H: --CH-- 10); 7.36 and 7.45 (2 broad t, J=8 Hz, 2H: --H 7 and --H 8); 7.51 and 7.87 (2 broad d, J=8 Hz, 2H: --H 6 and --H 9); 7.58 and 7.64 (2s, 1H each: --H of the imidazole); 8.44 (s, 1H: --CH=O); 8.78 (d, J=8.5 Hz, 1H: --CONH at 10); 12.50 (broad s, 1H: --CONH-- of the ring)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[O:60][C:59]([C:61]3[C:66]([F:67])=[CH:65][CH:64]=[CH:63][C:62]=3[F:68])=[N:58][C:57]=2[C:69]#[N:70])=[CH:51][CH:50]=1>CN(C=O)C>[C:69]([C:57]1[N:58]=[C:59]([C:61]2[C:62]([F:68])=[CH:63][CH:64]=[CH:65][C:66]=2[F:67])[O:60][C:56]=1[NH:55][C:52]1[CH:51]=[CH:50][C:49]([NH:48][C:11](=[O:13])[CH2:10][CH2:9][N:8]([CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:54][CH:53]=1)#[N:70]
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(N)cc1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC(=O)Nc1ccc(Nc2oc(-c3c(F)cccc3F)nc2C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-3-methylaminopropanoic acid (0.022 g, 0.11 mmol) in DMF (1.25 ml) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.040 g, 0.11 mmol) and diisopropylethylamine (0.018 ml, 0.11 mmol) followed by 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.030 g, 0.10 mmol) and the resultant mixture stirred at room temperature overnight. A further portion of N-(tert-butoxycarbonyl)-3-methylaminopropanoic acid (0.022 g, 0.11 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.040 g, 0.11 mmol) and diisopropylethylamine (0.018 ml, 0.11 mmol) was added and the reaction stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 3-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenylamino)-3-oxopropyl(methyl)carbamate (0.021 g, 0.04 mmol, 44%) as a white solid. LCMS (2) Rt: 3.03 min; m/z (ES+) 498.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:24][CH:23]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1-c1c(Br)cnn1C
Yield: 85 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with α,α,α-trifluoro-p-tolyl isocyanate (0.024 g, 19.0 μL, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 12 (0.048 g, 0.102 mmol, 83%) as a white solid. LCMS m/z (%)=469 (M+H79Br, 92), 471 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.51 (s, 1H), 8.27 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.71 (dd, J=2.3, 9.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.52 (s, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:11]1[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][N:12]=1)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([C:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:17]([OH:19])[NH:2][N:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(O)c1cccnc1C(=O)c1ccccc1
Product: OC1NN=C(c2ccccc2)c2ncccc21
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
A 3M ethanolic solution of hydrazine (20 ml, 60 mmol) is added to an ethanolic solution of 2-benzoyl-3-pyridine carboxylic acid (4.54 g, 20 mmol), and the mixture is stirred at room temperature for 5-24 hours. Precipitation yields 4-phenyl-1,2-dihydro-5-azaphthalazin-1-ol.
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([Cl:18])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16]([F:17])[C:2]=2[Cl:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OCc1c(Cl)ccc(F)c1Cl
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A stirring solution of 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.07 g, 0.03 mol) in acetonitrile was cooled to 0° C. using an ice bath. To this solution was added N-bromosuccinimide (NBS) (5.33 g, 0.03 mol) portionwise. The reaction was stirred at 0° C. for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc (500 mL), and purified via silica gel chromatography. The solvents were then removed in vacuo to yield 5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (5.8 g, 0.015 mol, 51%) as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) δ1.85-1.95 (d, 3H), 4.7-5.0 (brs, 2H), 5.9-6.01 (q, 1H), 6.8-6.95 (d, 1H), 7.01-7.2 (t, 1H), 7.4-7.45 (m, 1H), 7.8-7.85 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][N:22]=[CH:23][CH:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[N:22]1[NH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccn[nH]3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2ccc(N3CCNCC3)nc2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of step b) (0.11 g) is dissolved slowly in 3.5 ml of trifluoroacetic acid at 0° C. The resulting product is then left to stir for 2 hours at ambient temperature. The trifluoroacetic acid is evaporated off under vacuum and 0.065 g of the title compound is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:47])[C@@H:10]([NH:23][C:24](=[O:46])[C@@H:25]([NH:38]C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:48]>O1CCOCC1>[ClH:48].[ClH:48].[ClH:48].[CH2:1]([O:8][C:9](=[O:47])[C@@H:10]([NH:23][C:24](=[O:46])[C@@H:25]([NH2:38])[CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
The above prepared (S)-2-((S)-2,6-bis-tert-butoxycarbonylamino-hexanoylamino)-6-tert-butoxycarbonylamino-hexanoic acid benzyl ester (4.516, 6.793 mmol) was dissolved in 4 mol/L HCl in dioxane. After a couple of minutes, gas evolved and a precipitate was formed. After 3 h at ambient temperature, the reaction mixture was carefully evaporated and scrupulously dried to yield 3.81 g of the title compound as an off-white foam which was used without further purification for Example 13. E. GalNAc Cluster benzyl ester above. MS (ISP): 365.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][Cl:22])[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCCCCCCOc1ccnc(CCl)c1C
Yield: 90.2 %

Procedure:
16.0 g (0.05 mol, 1.0 eq.) of 4-nonyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 320 mL of ethyl acetate, and 6.5 g (0.055 mol, 1.1 eq.) of thionyl chloride was added dropwise at 8 to 12° C. Subsequently, the mixture was allowed to react for 0.5 hours at room temperature, and then a 7% aqueous solution of sodium bicarbonate (200 g) was added to adjust the reaction liquid to pH 7.5. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate (160 g), dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 12.8 g of 4-nonyloxy-2-chloromethyl-3-methylpyridine as a black oily matter.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C:10]3[CH:11]=[C:12]([CH3:22])[CH:13]=[CH:14][C:15]=3[C:16]([CH3:21])([CH3:20])[O:17][C:18]=2[CH:19]=1.CC(C)=O>C([O-])(O)=O.[Na+].O1CCOCC1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:10]3[CH:11]=[C:12]([CH3:22])[CH2:13][CH2:14][C@H:15]3[C:16]([CH3:21])([CH3:20])[O:17][C:18]=2[CH:19]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccc(C)cc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Reaction time: 0.17 h

Procedure:
One hundred mg of human IgG were dissolved in 7 ml of 0.2M NaHCO3, pH 9.6, and 108 mg of a cannabinol derivative having the formula ##STR5## in 2 ml of dioxane were added. Nine additional ml of dioxane were added, and the mixture was mixed intermittently for 4 hours at 4° C., after which 180 ml of cold acetone were added. The mixture was centrifuged for 10 minutes at 2,000×g, and the pellet was washed once with 20 ml of cold acetone. Following centrifugation for 10 minutes at 2,000×g, the pellet was resuspended in 10 ml of phosphate buffered saline (PBS). Dialysis was carried out for 3 days at 4° C. against 2 changes per day of 1000-ml volumes of PBS, to produce a THC-human IgG conjugate.