Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:34]([Cl:35])=[CH:33][C:27]([C:28](OCC)=[O:29])=[CH:26][N:25]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CO.[Na].[K]>CCCCCC.C1COCC1>[Cl:35][C:34]1[C:24]([NH:23][C@@H:20]2[CH2:21][CH2:22][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19]2)=[N:25][CH:26]=[C:27]([CH2:28][OH:29])[CH:33]=1
Reactant: CCOC(=O)c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(CO)cc2Cl)C1
Temperature: 7.5 °C
Yield: 41.5 %

Procedure:
A solution of diisobutylaluminium hydride in hexane solution (0.93M) (138 ml) was added to dropwise a solution of ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5-chloronicotinate (15.9 g) in THF (200 ml) with stirring at 0-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20° C. for 4 hours. The reaction mixture was cooled at 5° C. and MeOH (10 ml) was added and the reaction mixture was stirred at ambient temperature for 20 minutes. The potassium sodium tatarate tetrahydrate (36.4 g) was added to a above solution and the resultant mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate (5.85 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[S:13][C:12]([CH3:14])=[CH:11][C:9]=2[N:10]=1.C(N(CC)CC)C>C(O)C>[Cl:4][C:5]1[N:6]=[C:7]([N:2]([CH3:3])[CH3:1])[C:8]2[S:13][C:12]([CH3:14])=[CH:11][C:9]=2[N:10]=1
Reactant: Cc1cc2nc(Cl)nc(Cl)c2s1
Reactant: CNC
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc2nc(Cl)nc(N(C)C)c2s1
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.15 g) in ethanol (5 mL) were added 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (0.25 g) and triethylamine (0.12 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine and then dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure and crystallized with diethyl ether to obtain 2-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amine (0.16 g). (2) To a mixture of 2-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amine (0.150 g), Pd2(dba)3 (0.033 g), (±)-BINAP (0.067 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.26 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.21 g) under nitrogen atmosphere, and the mixture was stirred at 60° C. for 5 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain light yellow amorphous 1-((3R,4R)-3-(4-dimethylamino-6-methylthieno[3,2-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.097 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][OH:14].CCN(CC)CC.[Cl:22][C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][O:14][C:23]([Cl:22])=[O:24]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)OCCc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
For 5 min, a solution of 2-(2,4-dichloro-6-nitrophenyl)ethanol (500 mg, 2.12 mmol) and Et3N (214 mg, 2.12 mmol, dist. over KOH) in THF (5 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (503 mg, 2.5 mmol) in THF (5 ml, see above). It was stirred for 1 h while being cooled in an ice bath and stirred for 2 h at room temperature. The mixture was then filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2,4-dichloro-6-nitrophenyl)ethoxycarbonyl chloride (597 mg, 94%) as a bright yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+].CB(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:25])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 403.6 %

Procedure:
To 2,3-dichloro-5-trifluoromethylpyridine (25 g) were added 1-BOC-piperazine (23.84 g), potassium carbonate (32.08 g), N,N-dimethylformamide (50 mL) and toluene (50 mL), and the mixture was stirred at 100° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (45.71 g). To 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g) were added palladium (II) acetate (0.726 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.692 g), potassium fluoride (15.06 g), methylboronic acid (7.88 g) and tetrahydrofuran (300 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g). To 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g) were added 4N hydrogen chloride/ethyl acetate (26 mL) and chloroform (64 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and sodium hydrogen carbonate, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (6.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][C:32](O)=[O:33])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[CH3:35][N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.CN.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][C:31](=[C:32]=[O:33])[NH:36][CH3:35])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCCC2CCC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=C=O)CC1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 35 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[(2R/S)-2-(hydroxycarbonylethyl)pyrrolidin-1-ylcarbonyl]benzamide, TBTU, diisopropylethylamine, and methylamine in tetrahydrofuran. Yield: 35%; Rf value: 0.38 (silica gel: dichloromethane/ethanol=9:1); C25H27Cl2N5O3 (516.426); mass spectrum: (M+H)+=516/518/520 (chlorine isotope).
Reaction SMILES: [OH:1][CH:2]([C:20]1[S:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[C:7]([CH3:19])[CH:6]=1.[H-].[Na+].I[CH3:38]>>[CH3:38][O:1][CH:2]([C:20]1[S:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:23][CH:24]=1)[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH3:19])[C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[C:16]([CH3:18])[CH:17]=1
Reactant: CI
Reactant: Cc1cc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1OC(C)(C)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: COC(CCc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(4-(3-Methoxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid is prepared from 2-(4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid using 2.1 equivalents of sodium hydride and 2.1 equivalents of iodomethane according to general procedure H.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CCN(C(C)C)C(C)C.[C:28](O)(=[O:30])[CH3:29].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH:18][C:28](=[O:30])[CH3:29])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(=O)Nc1ccc2nc(-c3ccccc3Cl)[nH]c2c1
Reaction time: 8 h

Procedure:
To a vial containing a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5-ylamine in dioxane (0.2 M, 0.10 mL) was added DIPEA (0.5 M in toluene, 0.050 mL) and acetic acid (0.2 M in toluene, 0.12 mL), followed by BOP reagent (0.2 M in DMF, 0.15 mL). After overnight at ambient temperature, the mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to N-[2-(2-Chloro-phenyl)-3H-benzoimidazol-5-yl]-acetamide: MS (m/z) 320.02 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[N+]([C:19]1[CH:20]=C2C(=[CH:27][CH:28]=1)C(=O)C=CC2=O)([O-])=O.C=CC=C.ClC=C(Cl)Cl>O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[C:7]1[CH2:20][CH2:19][CH2:28][CH2:27][C:8]=1[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: O=C1C=CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: C=CC=C
Solvent: O
Solvent: ClC=C(Cl)Cl
Product: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 88 %

Procedure:
41.3 g of a crude 5-nitronaphthoquinone cake (having a water content of 40 wt% and a dry weight of 24.8 g, and comprised of 75 wt% of 5-nitronaphthoquinone and 15 wt% of 6-nitronaphthoquinone when determined under dried conditions), 13.1 g of 1,3-butadiene and 124 g of trichloroethylene were introduced into an autoclave. The autoclave was hermetically sealed and the reaction was effected at 80°C for 2.5 hours. Then, Example 1 was repeated to obtain 20.7 g of 5-nitrotetrahydroanthraquinone. The yield was 88.0%. The thus obtained 5-nitrotetrahydroanthraquinone was oxidized and reduced in accordance with the standard method to obtain 1-aminoanthraquinone having a purity above 98 wt% and a 2-aminoanthraquinone content of 0.5 wt%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH:6]([CH3:7])[CH2:5][CH2:13][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CCCC(C)OC(=O)c1ccc(OC(C)=O)cc1
Yield: 51.1 %

Procedure:
4-Acetoxybenzoic acid (6.2 g) was added to 25 ml of thionyl chloride, and the reaction was conducted under reflux for 10 hours. After excess thionyl chloride was distilled off, 15 ml of pyridine and 90 ml of toluene were added. Two grams of optically active S-(+)-2-pentanol was added dropwise thereto. After the addition, the mixture was heated under reflux for 4 hours, left to cool and diluted with 500 ml of chloroform. The organic layer was washed with dilute hydrochloric acid, a 1N sodium hydroxide aqueous solution and water in this order, and dried with magnesium sulfate. Further, the solvent was evaporated to obtain 2.2 g of a final crude compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][N:14]=2)[N:12]=1.B(Br)(Br)Br>>[OH:19][C:18]1[C:13]([C:11]2[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[O:9][CH:10]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CCCCc1nc(-c2ncccc2OC)co1
Agent: BrB(Br)Br
Product: O=C(O)CCCCc1nc(-c2ncccc2O)co1

Procedure:
Treat 5-[4-(3-methoxy-pyridin-2-yl)-oxazol-2-yl]-pentanoic acid methyl ester with boron tribromide followed by standard hydrolysis to afford the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[I-].[K+].[CH3:27][CH:28]=[CH:29][CH2:30][NH2:31]>O1CCCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH:31][CH2:30][CH2:29][CH:28]=[CH2:27])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(SC)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 32, 8-(methylthio)-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-(methylthio)-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)=[N:21][C:20]=3[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2c(O)cccc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1cccc2c1ccn2CC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 3 c], (4-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 3 b]) was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[NH:5][C:4](=O)[CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(Nc2nc(C)cc(=O)[nH]2)cc(OC)c1OC
Product: COc1cc(Nc2nc(C)cc(Cl)n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
6-Methyl-2-(3,4,5-trimethoxyphenylamino)-4(3H)pyrimidinone (1.0 g, 3.63 mmol) was dissolved in phosphoryl chloride and heated to 100° for 2 h. The mixture was cooled to room temperature and evaporated in vacuo to a viscous oil. The oil was dissolved in CH2CH2 (50 ml) and washed twice with saturated aqueous NaHCO3, the organic phases dried (MgSO4) and concentrated in vacuo. The residue was subjected to column chromatography (silica, 2% methanol/CH2CH2) to afford the title compound as an off white solid (1.03 g). A small amount was recrystallised from ethyl acetate to give fine off-white needles. m.p. 195-196°. δH (CDCl3) 2.40 (3H, s), 3.82 (3H, s), 3.88 (6H, s), 6.64 (1H, s), 6.95 (2H, s), and 7.07 (1H, br s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: CO
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc(O)ccc2c1
Yield: 84 %

Procedure:
A solution of 15.7 g (83.4 mmol) of 6-hydroxy-2-naphthoic acid is refluxed for 8 hours in a mixture of 160 ml of methanol and 8 ml of concentrated sulfuric acid. After cooling, the product precipitates out. After filtration and washing with isopropyl ether, 14.1 g of methyl 6-hydroxynaphthalene-2-carboxylate are obtained in the form of a beige-colored solid in a yield of 84%.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:16])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)C.[NH3:17]>C(O)C>[ClH:1].[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH2:16])=[NH:17])=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: N
Reactant: CCOC(=N)c1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: N=C(N)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
4-Amino-3-nitro-benzimidic acid ethyl ester hydrochloride (84.5 g, 344 mmol) was suspended in absolute ethanol (750 mL) and then cooled to 0° C. Ammonia was then passed through the solution for a period of 2 h. The flask was tightly sealed and allowed to warm up to room temperature over an 18 h period with stirring. The product was crystallized with diethyl ether and the resulting solid was filtered, washed and dried to give 4-amino-3-nitrobenzamidine monohydrochloride (70.7 g) as an off-white powder.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(N)CC.[CH3:18][C:19](=[CH:21][CH2:22][CH2:23][C:24](=[CH:26][CH:27]=O)[CH3:25])[CH3:20]>C1(C)C=CC=CC=1>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:5]=[C:3]([OH:4])[C:2]2[CH:27]=[CH:26][C:24]([CH2:23][CH2:22][CH:21]=[C:19]([CH3:20])[CH3:18])([CH3:25])[O:13][C:1]=2[CH:12]=1
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CCCCCc1cc(O)cc(O)c1
Solvent: CCCN
Solvent: Cc1ccccc1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(CCC=C(C)C)C=C2
Reaction time: 7 h

Procedure:
The reaction of 5 g. olivetol (27.8 mmole), 1.652 g. n-propylamine (2.3 ml., 27.8 mmole) and 4.6 ml. citral (27.8 mmole) in 55 ml. toluene was carried out in the same manner as described under Example 1. The refluxing time was 7 hours. Gas chromatographic analysis of the reaction mixture showed 61.62% CBC, 4.01% Cannabicitran and trace amount of iso-CBC.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)[C:12]=2[OH:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:26]([C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[O:29])[NH2:27]>C(O)(C)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:27][NH:26][C:28]([C:30]3[CH:31]=[CH:32][C:33]([S:36]([NH:39][CH3:40])(=[O:37])=[O:38])=[CH:34][CH:35]=3)=[O:29])[C:12]=2[OH:25])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cn1nc(C(=O)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Reactant: CNS(=O)(=O)c1ccc(C(=O)NN)cc1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(C(=O)NN=C(c2ccccc2)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 21.9 %

Procedure:
[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl)methanone (0.254 mmol, 85 mg), 4-(hydrazinocarbonyl)-N-methylbenzenesulfonamide (0.254 mmol, 58 mg) and p-tosylic acid monohydrate (30 mol %, 13 mg) were dissolved in isopropyl alcohol (8.5 mL) and stirred at 100° C. for 19 hours. Then, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (30.3 mg, yield 22%).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:22])[NH:10]2)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:22])[NH:10]2
Reactant: CC(=O)Oc1ccc(OC2CCCCO2)c2c1CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2c(O)ccc(OC3CCCCO3)c2N1

Procedure:
9.16 Grams of 5-acetoxy-8-tetrahydropyranyloxy-3,4-dihydro-2(1H)-quinolinone was dissolved in 200 ml of methanol, to this solution was added 45 ml of an aqueous solution of 10%-potassium carbonate, refluxed by heating for 1 hour, then concentrated to dryness under reduced pressure, there was obtained 5-hydroxy-8-tetrahydropyranyloxy-3,4-dihydro-2(1H)-quinolinone. This product was suspended in 100 ml of DMF, further 4.1 g of potassium carbonate was added to this suspension and stirred. To this mixture was added 3 ml of allyl bromide at room temperature and stirred for 8 hours. To this reaction mixture was added 200 ml of water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane, there was obtained 6 g of 8-tetrahydropyranyloxy-5-allyloxy-3,4-dihydro-2(1H)-quinolinone as white solid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.I[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]([CH2:9][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CCCCI
Reactant: COc1ccc(N)cc1
Product: CCCCN(CCCC)c1ccc(OC)cc1
Yield: 91.7 %

Procedure:
4-Methoxyaniline (10.5 g) in iodobutane (50 g) was heated under reflux overnight. Excess iodobutane was distilled off and final traces were removed in vacuo. The residue in DMF (dimethyl formamide) (50 mL) was treated with DABCO (1,4-diazobicyclo[2.2.2]octane) (20 g) and the mixture heated under reflux for 2 hours. Most of the DMF was then evaporated and the residue taken up in ethyl acetate, washed well with water, and dried (Na2SO4). After evaporation of the solvent the above procedure was repeated with iodobutane (50 mL) (overnight) followed by treatment with DABCO (10 g). After work-up, the resulting oil was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to give 4-methoxy-N,N-dibutylaniline (9.2 g).