Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][CH3:28])[N:26]=2)[N:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:10]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[CH2:27]([C:25]1[N:26]=[C:22]([C:12]2[N:11]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:10]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:9]([OH:8])[C:13]=2[OH:14])[S:23][CH:24]=1)[CH3:28]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2nc(CC)cs2)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(O)c(O)c(-c2nc(CC)cs2)n1-c1ccc(OC)cc1
Yield: 64.4 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-5-(4-ethylthiazol-2-yl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (30) (70 mg, 0.12 mmol) in MeOH/THF (3:1; 5 mL) was passed through a Thales ‘H-cube’ cartridge (10 Pd/C) at a flow rate of 1 mL/min at 40° C. under H2 (full H2 mode). The output was concentrated in vacuo and the resulting oil was purified by silica gel chromatography (12 g, 0-20% EtOAc in isohexane) to afford ethyl 5-(4-ethylthiazol-2-yl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-086) (30 mg, 63%) as an off-white solid: m/z 389 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 8.68 (s, 1H), 7.28-7.19 (m, 2H), 7.06-7.03 (m, 1H), 7.03-6.97 (m, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([OH:18])=O)[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>ClCCl>[CH:25]1([NH:28][C:16]([C:11]2[C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][C:14]=3[NH:13][N:12]=2)=[O:18])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: O=C(NC1CC1)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Starting with a mixture of 1.23 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid, 0.26 cm3 of cyclopropylamine, 0.86 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 60 mg of hydroxybenzotriazole in solution in 30 cm3 of dichloromethane, and after stirring for 18 hours at a temperature in the region of 20° C., washing with twice 30 cm3 of distilled water and purifying the crude product obtained by flash chromatography on silica gel (30–70 μm), eluting with a cyclohexane/ethyl acetate (60/40) mixture, 0.58 g of (N-cyclopropyl)-6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxamide is obtained in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[N:7]=[N+:8]([O-:17])[C:9]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=2[N:11]=1>C(O)(C(F)(F)F)=O>[OH:2][C:6]1[N:7]=[N+:8]([O-:17])[C:9]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: Nc1nc2ccc(O)cc2[n+]([O-])n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(O)nc2ccc(O)cc21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Sodium nitrite (22 mmol) was added in small portions to a stirred solution of 3-amino-7-hydroxybenzo[e][1,2,4]triazine 1-oxide (20 mmol) in TFA (40 mL) at 5° C., and the solution stirred at 20° C. for 3 h. The solution was poured into ice/water (400 mL), stirred 30 min, filtered, washed with water (3×10 mL) and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(F)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 3 parts of 1-(4-fluoro-2-hydroxyphenyl)ethanone, 14.9 parts of (chloromethyl)benzene, 16.4 parts of potassium carbonate, 0.1 parts of potassium iodide and 120 parts of 2-propanone was stirred overnight at reflux temperature. The reaction mixture was evaporated. The reaction mixture was poured into water. The product was extracted three times with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and water. The product was filtered off and dried, yielding 11 parts (58%) of 1-[4-fluoro-2-(phenylmethoxy)phenyl]ethanone (intermediate 76).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(F)cc1
Yield: 63.2 %

Procedure:
Fluorobenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17 mol) were added to 500 mL of methylene chloride, and the reaction mixture was stirred. Succinic anhydride (50 g, 500 mmol) was added to the stirring reaction mixture all at once, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by cautious addition of 10% HCl, and the reaction mixture was added to 500 mL of water. The aqueous mixture was extracted twice with 250 mL of methylene chloride, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to give 62 g (316 mmol, 59.6%) of 4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)+.
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([F:17])([F:16])[C:8]2=[O:18])[CH2:4]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([F:17])([F:16])[C:8]2=[O:18])[CH2:4]1
Reactant: N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cccnc32)C1
Reactant: Clc1nc2ccccc2s1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C1N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncccc2C1(F)F
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1-(Trans-3-aminocyclobutyl)-3,3-difluoro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrobromide (0.084 g, 0.262 mmol), 2-chlorobenzothiazole (0.0534 g, 0.315 mmol), and N,N-diisopropylethylamine (0.183 mL, 1.050 mmol) were mixed in DMSO (0.5 mL) in a sealed tube. The reaction mixture was stirred at 120° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.030 g, 0.081, 30.7% yield) as a white solid. M+1: 373.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39-2.49 (m, 2 H) 3.19-3.30 (m, 2 H) 4.48-4.58 (m, 1 H) 5.10 (quin, J=8.36 Hz, 1 H) 7.04 (t, J=7.53 Hz, 1 H) 7.21-7.26 (m, 1 H) 7.29 (dd, J=7.34, 5.38 Hz, 1 H) 7.43 (d, J=7.82 Hz, 1 H) 7.70 (d, J=7.24 Hz, 1 H) 8.20 (dd, J=7.43, 1.37 Hz, 1 H) 8.51-8.56 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:6]([CH:8]=1)[NH2:7].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:6]([NH:7][S:27]([C:19]2[O:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=2)(=[O:28])=[O:29])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1SCCc1ccccn1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCCc1ccccn1)c1cc2ccccc2o1

Procedure:
Following General Procedure B, the title compound was prepared from 5-chloro-2-((2-(pyridin-2-yl)ethyl)thio)aniline (439 mg, 1.663 mmol) and benzofuran-2-sulfonyl chloride (2×359 mg, 2×1.663 mmol) in pyridine (5 ml).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=[O:24])=[CH:18][CH:17]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:23]([OH:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: O=CCc1ccc(F)cc1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1
Product: N#Cc1ccc(C(C(O)Cc2ccc(F)cc2)n2ccnc2)cc1

Procedure:
1-[1-(4-cyanophenyl)-3-(4-fluorophenyl)-2-hydroxypropyl]-1H-imidazole is prepared according to the procedure of Example 1 using 1-(4-cyanobenzyl)-imidazole and 4-fluorophenylacetaldehyde as starting materials. The product is purified by flash chromatography.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>C1COCC1.C1OCCOCCOCCOCCOCCOC1>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[C:2]([CH3:4])[CH3:3])=[CH:33][CH:32]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)=Cc1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
To a stirred slurry of 17.29 g (40.0 mmol) of isopropyltriphenylphosphonium iodide and 500 mg (2 mmol) of 18-crown-6 in 100 mL of THF under nitrogen at 5° C. was added 4.50 g (40.0 mmol) of potassium t-butoxide over 5 minutes. The resulting deep red-orange slurry was stirred 10 minutes and then a solution of 6.50 g (35.0 mmol) of p-bromobenzaldehyde in 40 mL of THF was added at a rate to keep the temperature below +10° C. The resulting bright yellow slurry was stirred for 20 minutes and then poured into 300 mL of hexanes. The solids were filtered off and the filtrate evaporated. This residue was purified by flash chromatography (5×15 cm column) and eluted with hexanes to provide 5.66 g (77%) of title compound as a colorless oil.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[Br:8].[N:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[Br:8][C:4]1[N:3]([O:2][C:15]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:16])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1ccnc1Br
Agent: Cl
Product: O=C(On1ccnc1Br)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-2-bromoimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (98%, crystals).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(NCC(F)(F)F)CC2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)ccc2c1CCC(NCC(F)(F)F)CC2
Yield: 34.9 %

Procedure:
In an analogous procedure to Example 651, part c, 1-Methoxy-N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide to yield 2-{5-Chloro-2-[1-methoxy-7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (36.29, 34.9% yield) as a beige foam. 9.40 (s, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.61 (m, 1H), 7.47 (s, 1H), 6.82 (d, J=8.2 Hz, 1H), 3.73 (s, 3H), 3.25 (m, 3H), 2.87 (m, 2H), 2.75 (s, 6H), 2.66 (m, 1H), 2.50 (m, 1H), 2.10 (m, 2H), 1.54 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:13])=[C:9]([CH2:11][OH:12])[N:10]=1.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:13])=[C:9]([CH2:11][O:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1CO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of [2-(2-furyl)-5-methyl-4-oxazolyl]methanol (5.18 g), 6-chloro-3-cyanopyridine (4.00 g) and N,N-dimethylformamide (100 ml) was added sodium hydride (60% in oil, 1.27 g) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]nicotinonitrile was obtained as colorless crystals (6.97 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 105–106° C.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>P(Cl)(Cl)(Cl)=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]2[N:1]3[CH2:2][CH2:3][C:4]4[C:9]3=[C:8]([CH:7]=[CH:6][CH:5]=4)[C:18]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[N:17][C:11]=2[CH:12]=1
Reactant: CN1CCN(C(=O)Nc2cc(F)ccc2N2CCc3ccccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cc(F)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
A stirred mixture of 10.6 g (0.030 mole) of N-[2-(2,3-dihydro-1H-indol-1-yl)-5-fluorophenyl]-4-methyl-1-piperazine carboxamide of Example 2c in 250 ml of phosphorus oxychloride was refluxed for 6 hours under nitrogen, then cooled to room temperature. The excess phosphorus oxychloride was removed at aspirator pressure with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture) and then treated first with 250 ml of ice-cold 2N-NaOH, then with 500 ml of dichloromethane. The mixture was stirred vigorously until all the material passed into solution. The organic phase was separated, washed thrice with water, dried over Na2SO4 and concentrated in vacuo to 9.1 g of an oil. This material was adsorbed on a tall chromatography column containing 400 g of alumina made up in CH2Cl2. Elution with CH2Cl2 brought forth fractions of pure tetracycle which were combined and concentrated to afford 3.5 g (35% overall yield) of product which crystallized. This was recrystallized from a small volume of acetone to furnish 2.1 g of 9-fluoro-6-(4-methyl-1piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine, m.p. 151°-153° C.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[C:6]2=[O:15].C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1C=CC=CC=1>[CH3:12][O:11][C:10]1[CH:2]=[C:3]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=1)[C:6](=[O:15])[N:5]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=1)[CH2:4]2
Reactant: COc1cc(OC)c2c(c1Br)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a solution of 4-bromo-5,7-Dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1 one (0.200 g, 0.45 mmol) in benzene under N2 atmosphere was added 2,2′-azobis(2-methyl proponitrile) AIBN (5.0 mg), followed by tributyl tin hydride (0.238 mL, 0.9 mmol). The resulting mixture was refluxed in an oil bath for 2 h. The reaction was monitored by GC-MS for the disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 min. The solids were filtered and the filtrate was concentrated. The resulting material was purified using column chromatography (typically 40% ethyl acetate in hexanes) to give 5,7-Dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1one (0.106 g, 64%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.82 (s, 3H), 3.95 (s, 3H), 4.17 (s, 2H), 4.72 (s, 2H), 6.43 (d, 2H), 7.16 (d, 2H), 7.32 (d, 2H). GC-MS: m/z 367 (M)+, 349 (M-18)+.
Reaction SMILES: [CH:1]([C@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH3:12])[C:6]([O:13][CH3:14])=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.I[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:28][C:27]=2[CH:36]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC.CCOC(C)=O>[CH:1]([C@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@:7]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:30][C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:28][C:27]=3[CH:36]=2)([CH3:12])[C:6]([O:13][CH3:14])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCCCCc1nc2cc(CCI)ccc2o1
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCc1nc2cc(CC[C@@]3(C)N=C(OC)[C@H](C(C)C)N=C3OC)ccc2o1
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, a −70° C. solution of (S)-2-Isopropyl-3,6-dimethoxy-5-methyl-2,5-dihydro-pyrazine (652.5 μl, 3.291 mmol) in dry THF (7 ml) was treated with a solution of n-butyl lithium in n-hexane (2.1 ml of a 1.6M solution, 3.29 mmol). After stirring for 10 minutes a solution of 5-(2-iodo-ethyl)-2-pentyl-benzoxazole (753 mg, 2.19 mmol) in dry THF (5 ml) was added and the reaction mixture was stirred for 90 minutes at −65° C. followed by 2 hours at 0-5° C. The reaction was distributed between AcOEt and saturated aqueous ammonium chloride. The organic layer dried over MgSO4 and concentrated in vacuum. Silica-gel flash chromatography (pentane/diethyl ether 4/1) provided the crude 5-[2-((2R,5S)-5-Isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydro-pyrazin-2-yl)-ethyl]-2-pentyl-benzoxazole. The crude product was dissolved in acetonitrile (21 ml) and treated with water (21 ml) and trifluoroacetic acid (450 μl) and stirred for 3 days at RT. The solvents were removed in vacuum and the title compound was obtained after reversed phase chromatography (Waters, C-18, eluent: gradient of water/acetonitrile containing 0.1% trifluoroacetic acid) as an amorphous solid. 1H-NMR (CDCl3) δ: 8.50 (s; 1H), 6.98 (s; 1H); 8.86/6.83 (2 broad singlets; 2H), 3.71 (s; 3H), 2.75-2.35 (m; 4H), 2.20 (broad s; 2H), 1.70 (broad s; 2H), 1.61 (s; 3H), 1.40-1.20 (m; 4H), 0.90 (m; 3H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([OH:18])=[C:9]([C:15](=[O:17])[CH3:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:21](=O)(OCC)[O:22]CC.Cl.CC(C)([O-])C.[K+]>O>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]3[C:8]=2[O:18][C:21](=[O:22])[CH:16]=[C:15]3[OH:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C)=O)c(O)c1OC1CCCC1
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [H-]
Solvent: O
Product: COc1ccc2c(O)cc(=O)oc2c1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[3-(Cyclopentyloxy)-2-hydroxy-4-methoxyphenyl]ethanone (4.25 g, 17 mmol) was added portionwise to a mixture of sodium hydride (1.4 g, 60%, 35 mmol) and diethyl carbonate (30 mL) at rt under N2. The reaction was refluxed for 1 h and then cooled to rt. 10% Hydrochloric acid (30 mL) was added, and the mixture was stirred for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (200 mL×2). The combined extracts were dried, filtered, concentrated, and redissolved in t-butanol (50 mL). Potassium t-butoxide (4.0 g, 36 mmol) was added, and the reaction was refluxed. After 42 h, additional potassium t-butoxide (2.0 g, 18 mmol) was added. After an additional 2 d, the reaction was allowed to cool to rt, concentrated, diluted with 1N HCl (100 mL), and extracted with ethyl acetate (200 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (3:2→0:1; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one: MS (ESI): 277.1.
Reaction SMILES: C([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13]O)(C)(C)C.CC(C)([O-])C.[K+]>C1COCC1>[NH:7]1[C@@H:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][O:15][C:6]1=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1N[C@@H]2CCC[C@@H]2CO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of ((1R,2S)-2-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (1.6 g, 7.43 mmol) in THF (40 ml) was added potassium tert-butoxide (3.34 g, 29.7 mmol, 4.0 equiv.) at room temperature. After stirring for 1 h at 60° C. the reaction was allowed to warm up to room temperature and after workup with Ethyl acetate/water, drying and concentration in vacuo, the crude material mixture was adsorbed on silica and chromatographed over a prepacked silica column (50 g, 50% to 100% EtOAc in Heptane gradient) to yield 950 mg (91%) of the title compound as a white solid, which was directly used in the next step.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([Cl:16])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc2c(c1)OCCO2

Procedure:
A mixture of 1,4-benzodioxane-6-carboxylic acid (0.5 g), benzene (20 ml) and thionyl chloride (5 ml) is heated for one hour under reflux. The reaction mixture is evaporated to dryness under reduced pressure. To the residue is added benzene (50 ml), then the solvent is again distilled off to leave 1,4-benzodioxane-6-carbonyl chloride. This compound dissolved in benzene (20 ml) is added dropwise, while stirring, to a mixture of 1-(3,4,5trimethoxybenzyl)piperazine dihydrochloride (1 g), triethylamine (1.5 g) and N,N-dimethylacetamide (20 ml), followed by stirring at room temperature for 30 minutes. To the reaction mixture are added water (100 ml), ethyl acetate (200 ml) and hexane (50 ml), then extraction is conducted. The extract is washed with water, dried, and concentrated under reduced pressure. The residue as purified by means of a silica gel column chromatography (hexane:acetone=1:1-2:3) to afford an oily product, which is dissolved in ethyl acetate. To the solution is added 1N hydrogen chloride - acetic acid solution (5 ml), and the mixture is left standing. The supernatant is removed by decantation, and the precipitates are recrystallized from ethyl acetate to give 1-(1,4-benzodioxan-6-ylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.7 g) as colorless prisms, m.p. 180°-185° C.