Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.C[O:26][C:27](=[O:50])[C@H:28]([C@@H:47]([CH3:49])O)[NH:29]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2([O:22][C@H:47]([CH3:49])[C@@H:28]([C:27]([OH:50])=[O:26])[NH2:29])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: C[C@@H](OC1(c2cccc(C(F)(F)F)c2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(3-trifluoromethylphenyl)-9H-fluoren-9-ol (Example 3m) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:34])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine (60 mg, 0.26 mmol), (4-benzyloxy-phenyl)-acetic acid (63 mg, 0.26 mmol), ethyldimethylpropylcarbodiimide hydrochloride (60 mg g, 0.31 mmol), N-hydroxybenzotriazole (42 mg, 0.31 mmol), and N-methyl morpholine (66 mg, 0.62 mmol) in 2 mL of DMF was shaken for 6 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 4H), 2.43 (m, 4H), 2.86 (t, 2H, J=6.78), 3.56 (s, 2H), 4.45 (t, 2H, J=6.78), 5.08 (s, 2H), 6.97 (m, 2H), 7.25–7.31 (m, 6H), 7.27 (m, 2H), 7.59 (m, 1H), 7.97 (s, 1H), 8.08 (s, 1H), 10.10 (s, 1H); MS (DCI/NH3) m/z 455 [M+H]+.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCc1ccc(C(O)C(=O)c2ccccc2)cc1
Yield: 74 %

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and ethylbenzene (0.49 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 2 hours. The reaction mixture was extracted with ethylacetate, the extract was washed with saturated sodium hydrogen carbonate solution and brine, dried with sodium sulfate anhydrous, and then concentrated to obtain a yellow-colored oil. The oil was crystallized from a petroleum ether/diethylether to obtain 357.1 mg (74.0% yield) of 4'-ethylbenzoin.
Reaction SMILES: C([C:3]1[CH:7]=[CH:6][O:5][N:4]=1)=O.[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20]C3OC=NC=3)[CH2:18][C@@H:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]([S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])[CH2:15][C:14]=2[CH:41]=1)#[N:9].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20][C:6]3[O:5][N:4]=[CH:3][CH:7]=3)[CH2:18][C@@H:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]([S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:35])[CH2:15][C:14]=2[CH:41]=1)#[N:9]
Reactant: CN(C)CCS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2cnco2)C[C@H]1Cc1ccccc1
Reactant: O=Cc1ccon1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2ccno2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-formylisoxazole (19.4 mg, 0.2 mmol) and Compound B of Example 25 (39.9 mg, 0.1 mmol) in DCM (0.5 mL) at rt was added TFA (45 mg, 0.4 mmol), followed by triethylsilane (35 mg, 0.3 mmol). The resulting mixture was stirred at rt for 1 hour, neutrallized with NaHCO3 solution and extracted with DCM (2×5 mL). The combined extract was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (SiO2; ethyl acetate: methanol ammonia/100:10:0.1) to afford the title compound, 45 mg (87%). MS: m/e (M+H)+=480.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[Li+].[CH3:24]C([N-]C(C)C)C>C1COCC1>[C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:24])[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1c2ccccc2CN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)c2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution N-BOC-1,3-dihydro-2H-isoindol-1-carboxylic acid, methyl ester (38 mmol) and MeI (10 mL, 160 mmol) in 150 mL of anhydrous THF at −30° C. was added LDA (Aldrich, 1.5 M in cyclohexane, 51 mL, 76.5 mmol). The reaction was allowed to warm up to rt over 4 h. The reaction was cooled to −30° C., and was quenched with saturated aqueous solution of NH4Cl (50 mL). The resulting mixture was partitioned between EtOAc and brine, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried with anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with 10:1 to 5:1 hexane/ether to afford N-BOC-1-methyl-1,3-dihydro-2H-isoindol-1-carboxylic acid, methyl ester.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([C:22](F)=[O:23])=[CH:12][N:11]=1.Cl>CN(C=O)C.O>[NH2:2][C:1]1[N:16]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[C:14]2[N:15]=[C:10]([Cl:9])[N:11]=[CH:12][C:13]=2[C:22](=[O:23])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CC(C)(O)CNc1nc(Cl)ncc1C(=O)F
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)Cn1c(N)c(C(N)=O)c(=O)c2cnc(Cl)nc21
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution, cooled to 2-5°C. on an ice bath, of 4.4 g (52.36 mmol) of cyanoacetamide in 70 mL of anhydrous DMF are added portionwise 4.19 g (104.72 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C., and this suspension is then added rapidly to a solution of 12.35 g (49.87 mmol) of the acid fluoride prepared in step 17.2 in 70 mL of anhydrous DMF, precooled to 2-5°C. The mixture is stirred overnight at room temperature and is then cooled to 2-5°C. on an ice bath, and 2.09 g (52.36 mmol) of 60% sodium hydride are added portionwise. The reaction mixture is stirred for 3 hours at room temperature and then poured into a mixture of ice, 100 mL of water and 150 mL of aqueous 1N HCl. The yellow precipitate formed is isolated by filtration, rinsed with water and then dried in an oven. After triturating in methanol and drying in an oven, 8.84 g of the expected product are finally obtained in the form of a yellow solid. Yield=57%.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH2:22][CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(C)=O>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH:16]([CH2:22][CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:3]=1
Reactant: CCCCC(Br)C(=O)OCC
Reactant: Brc1n[nH]c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC(C(=O)OCC)n1nc(Br)c(Br)c1Br
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A quantity (30.4 g., 0.1 mole) of 3,4,5-tribromopyrazole was dissolved in 500 ml. acetone and 27.6 g. (0.2 mole) solid anhydrous potassium carbonate was added. The mixture was heated at the reflux temperature with stirring for 10 minutes and after cooling 23.0 g. (0.11 mole) ethyl 2-bromohexanoate was added. This reaction mixture was heated at the reflux temperature for 11/2 hrs., cooled, and then filtered. The solids on the filter were washed with acetone and the combined acetone filtrate and acetone washes were evaporated to dryness under reduced pressure. Distillation of the residue yielded ethyl 3,4,5-tribromo-α-butylpyrazole-1-acetate, 41.0 g. (92% yield), having a boiling point at 138° to 140° C. at 0.15 mm. mercury pressure.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:6]1[C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=[CH:8][C:7]=1[NH2:10]
Reactant: Nc1ccc2ncsc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2ncsc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of benzothiazol-6-ylamine (6.4 g, 42.6 mmol) in glacial acetic acid (40 mL) was added bromine (2.18 mL) in glacial acetic acid (10 mL) dropwise. The reaction mixture was stirred at RT for 1 h. Water (160 mL) was added to the reaction mixture and the solid formed was extracted with ethyl acetate (3×40 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate solution (200 mL), water (100 mL), and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by column chromatography (20% ethyl acetate:hexanes) afforded 6.5 g (67%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 4.31 (br. s, 2H), 7.02 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.80 (s, 1H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][OH:15])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([O:15][CH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OCCC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of NaH (60% in oil, 43.6 g, 1.09 mol) in DMF (900 mL) is carefully added crude 2-(1,4-dioxaspiro[4.5]dec-8-yl)ethanol (139.5 g) in DMF (300 mL) at 0-5° C., and the mixture is stirred for 30 min at the same temperature. To the mixture is added dropwise benzyl bromide (129.6 mL, 1.09 mol) at 0-5° C., and stirring is continued for 1 hour at the same temperature. After addition of H2O (1000 mL), the mixture is extracted with EtOAc-Hexane (3:1, 1200 mL). The water layer is extracted with EtOAc-Hexane (3:1, 1200 mL×2), and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford crude 8-[2-(benzyloxy)ethyl]-1,4-dioxaspiro[4.5]decane. The crude product is used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[N:31]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[C:35]([F:41])[CH:34]=4)[CH:30]=[N:29][CH:28]=3)=[O:26])[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[N:31]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[C:35]([F:41])[CH:34]=4)[CH:30]=[N:29][CH:28]=3)=[O:26])[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(Cn2cncc2C(=O)N2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2C(=O)N2CCN(c3cccc4ccc(O)cc34)C(=O)C2)cc1F
Reaction time: 18 h

Procedure:
To a solution of the benzyl ether from Step B (430 mg, 0.77 mmol) in 10 mL of 1:1 MeOH/EtOAc was added 10% palladium on carbon (430 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature overnight. Another portion of Pd/C was added (400 mg). After another 18 hours, the solution was filtered through celite. Concentration in vacuo provided the titled product which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH2:1]([N:8]1[CH2:25][C@@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[C@H:9]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(C)O[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 1-benzyl 4-methyl(2S)-2-[benzyl((2R)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (34.30 g, 0.05464 mol) in a mixture of tetrahydrofuran (90.0 mL, 1.11 mol) and toluene (470.0 mL, 4.412 mol) at −78 Celsius was added 1.00 M of Lithium hexamethyldisilazide in tetrahydrofuran (65.6 mL). The resulting mixture was stirred at −78 Celsius overnight, and then allowed to warm up to at 0 Celsius gradually and stirred at 0 Celsius for 30 min. After quenched with aq ammonium chloride, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried (sodium sulfate), and concentrated to dry. The residue was purified on silica gel column, eluting with 0 to 20% EtOAc in hexane, to yield the cyclized product (19.47 g, 78.2%). MS (ESI): (M+H)+=456.0.
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([S:36]([O-:38])=[O:37])[CH:30]=[CH:29]3)=[CH:22][CH:21]=1.[Na+]>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([S:36]([C:2]2[C:10]4[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=4[CH:5]=[CH:4][CH:3]=2)(=[O:38])=[O:37])[CH:30]=[CH:29]3)=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(I)cccc21
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc2c(S(=O)(=O)c3ccc4cc(-c5ccc(F)cc5)ccc4c3)cccc21
Yield: 39.7 %

Procedure:
Prepared according to the method of Example 6 Step 4 using 4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.46 g, 1.23 mmol) and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (0.42 g, 1.36 mmol), to give the title compound as a colourless solid (260 mg, 39%). 1H NMR (500 MHz, CDCl3): δ 8.92 (1H, s), 8.21 (1H, dd, J=1.4, 8.6 Hz), 8.16 (1H, d, J=7.7 Hz), 8.07 (2H, d, J=9.9 Hz), 7.96 (1H, s), 7.91 (1H, d, J=8.7 Hz), 7.77 (2H, d, J=7.3 Hz), 7.64 (2H, dd, J=5.3, 8.5 Hz), 7.47 (1H, t, J=7.9 Hz), 7.17 (2H, t, J=8.6 Hz), 5.51 (2H, s), 4.12 (2H, q, J=7.1 Hz), 3.47 (2H, t, J=8.1 Hz), 2.04 (3H, s), 1.26 (3H, t, J=7.1 Hz), 0.86 (2H, t, J=8.1 Hz), −0.08 (9H, s); m/z (ES+) 534 [MH+].
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1.CC(C)N=C=NC(C)C.C1C=C2N=NN(O)C2=CC=1.O>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AM using 5-({cyclopropyl[(4-methoxy-2,6 dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (126 mg, 0.33 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (59 mg, 0.30 mmol), DIC (79 μL, 0.5 mmol) and HOBt monohydrate (76 mg, 0.5 mmol) in DCM (2.5 mL). The crude product was purified by FCC eluting with 95:5 DCM:7N NH3 in MeOH.
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: CCCCCc1cc(O)cc(O)c1
Reactant: CC(C)=CCCC(C)=CC=O
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: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.[C-:21]#[N:22].[K+].O>CS(C)=O>[C:21]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1CC#N
Temperature: 90 °C

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-(methylsulfonyloxymethyl)cyclohexyl]carbamate (1.8 g) in dry DMSO was added with potassium cyanide (0.52 g, 7.76 mL) and the mixture was then heated at 90° C. under N2 for 4 hours. The mixture was cooled and then poured on to water (50 mL) and extracted with ether (3×30 mL). The combined organic phases were washed with brine and concentrated in vacuo to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:12].[C:13]([O:17][C:18]([N-:20][S:21](N1C=CC(=[N+](C)C)C=C1)(=[O:23])=[O:22])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CCOC(C)=O.Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:12][S:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])(=[O:22])=[O:23]
Reactant: NC1CCc2c(F)ccc(F)c21
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NS(=O)(=O)NC1CCc2c(F)ccc(F)c21
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a solution of 4,7-difluoro-2,3-dihydro-1H-inden-1-amine (CAS No. 625471-13-8, 1.19 g, 11.2 mmol) in DCM (50 mL) were added [(tert-Butoxy)carbonyl]{[4-(dimethyliminio)pyridin-1(4H)-yl]sulfonyl}amide (3.70 g, 12.3 mmol) and TEA (4.66 mL, 33.5 mmol) at room temperature. The resulting solution was stirred for 75 hours at room temperature. The reaction mixture was diluted with AcOEt and 1N HCl and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to afford the title compound (3.82 g, 11.0 mmol).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:16])=O.CCCCCC>C(Cl)Cl>[Cl:16][C:4]1[C:3]([C:1]#[N:2])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2ccccc2[nH]c1=O
Solvent: CCCCCC
Solvent: ClCCl
Product: N#Cc1cc2ccccc2nc1Cl

Procedure:
A mixture of 50 g of 3-cyano-2(1H)-quinolinone and 250 ml of phosphoryl chloride was heated at reflux for 18 hours. Volatile material was evaporated from the mixture under reduced pressure and the resulting residue was carefully added to water. The solid which formed was separated by filtration, washed with water and dried to give crude product. This was dissolved in methylene chloride and the resulting solution was treated with silica gel and filtered to give a pale yellow solution. Hexane was added to the solution which was then placed on a steam bath until crystallization occurred. The solid was then separated by filtration to give 2-chloro-3-cyanoquinoline. This compound melts at about 163°-164° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>CCOCC>[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55]([O:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(CCCCCCCCCCCCOCc1ccccc1)CCCCCCCCCCCCOCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC(CCCCCCCCCCCCOCc2ccccc2)CCCCCCCCCCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
First, 3 g of bis(12-benzyloxydodecyl)methanol and 20 ml of pyridine were placed in a 100 ml flask. Then, 1.15 g of p-toluenesulfonylchloride was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ether. The diluted mixture was washed with diluted hydrochloric acid, aqueous sodium bicarbonate, and water in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was recrystallized from acetone to obtain 1.6 g of bis(12-benzyloxydodecyl)methyl p-toluenesulfonate (Y: 42%). The compound thus obtained had a purity of 98.5% by HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[O:13])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.Cl>CO.[C].[Pd]>[NH2:1][C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of 3-(4-nitrophenoxy)-N-[4-(trifluoromethyl)phenyl]benzamide (6.75 g, 16.8 mmol) in methanol (20 mL)/tetrahydrofuran (10 mL) were added 10%-palladium carbon (2 g) and concentrated hydrochloric acid (1 mL), and the mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 3 hr. The catalyst was filtered off through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was triturated with diethyl ether to give the title compound (5.37 g, 86%) as a white solid.