Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Br)=[CH2:12].Cl.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dichlorobenzaldehyde (7.5 g, 43 mmol) in THF (75 mL) was cooled to 0° C. and vinylmagnesium bromide (1M in THF, 48 mL, 48 mmol) was added dropwise. The reaction was warmed to room temperature and was stirred overnight. Aqueous HCl (1N) and EtOAc were added. The aqueous solution was extracted with EtOAc and the organic solution was dried (MgSO4), filtered, and concentrated. The residue was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.Cl.N[C@@H]1CC[CH2:16][CH2:15][C@H:14]1[OH:19].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.IC1COC1>CC(O)C.[Ni](I)I>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:15]2[CH2:14][O:19][CH2:16]2)[CH:3]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Brc1cncc(C2COC2)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 476.7 %

Procedure:
A mixture of (5-bromopyridin-3-yl)boronic acid (330 mg, 1.6 mmol), nickel(II) iodide (15 mg, 0.049 mmol), trans-2-amino-cyclohexanol hydrochloride (7 mg, 0.049 mmol) and sodium bis(trimethylsilyl)amide solution in THF (1M; 1.6 mL, 1.6 mmol) in 2-propanol (2 mL) is stirred under Ar for 10 min. 3-Iodo-oxetane (150 mg, 0.82 mmol) is added and the mixture is heated at 80° C. for 90 min. After cooling to room temperature, the mixture is filtered through diatomaceous earth, rinsing thoroughly with EtOH. The filtrate is concentrated to give crude product. Purification by flash column chromatography affords 50 mg of 3-bromo-5-oxetan-3-yl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][CH2:12][C:13](=O)[CH2:14][CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(C(F)(F)F)=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:9][CH:13]([CH2:14][CH3:15])[CH2:12][CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Cc1c(Cl)cnc(N)c1N
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)Nc1c(N)ncc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a room-temperature solution of 5-chloro-4-methylpyridine-2,3-diamine (200 mg, 1.27 mmol, 1.0 equiv) and 3-pentanone (400 uL, 3.78 mmol, 3.0 equiv) in THF (0.5 mL) and TFA (0.5 mL) was added sodium triacetoxyborohydride (807 mg, 3.81 mmol, 3.0 equiv) as a solid in one portion. The resulting mixture was allowed to stir overnight at room temperature. The reaction was then diluted with EtOAc and washed with saturated aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC to provide the title compound (49.4 mg, 17%). m/z=228.1 [M+H]+
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.4 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.22 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by crystallization (diethyl ether) yielded the title compound as an off-white solid (0.14 g, 65%). MS (ISP) 525.2 [(M+H)+]; mp 244° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: Fc1ccccc1CBr
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccccc2F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (38.2 mg, 0.081 mmol), 2-fluorobenzyl bromide (11.3 μL, 0.09 mmol, 1.05 equiv), and potassium carbonate (28.0 mg, 0.2 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 26.0 mg (56%). Mass spec.: 580.38 (MH)+.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[C:3]#[N:4].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>>[C:12]([C:15]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[NH:1][C:16]=1[CH3:17])(=[O:14])[CH3:13]
Reactant: CC(=O)CC(C)=O
Reactant: N#CC(N)c1ccc(F)cc1
Product: CC(=O)c1c(C)[nH]c(-c2ccc(F)cc2)c1N

Procedure:
Starting from 2-amino-2-(p-fluorophenyl)acetonitrile and acetylacetone, the open-chain intermediate compound is obtained; b.p. 150° C./0.3 mm Hg. Overall yield of the title compound: 47%, m.p. 211°-12° C. (from ethanol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.C(N(CCCC)CCCC)CCC.[C:25]([OH:29])(=[O:28])[CH:26]=[CH2:27].Cl>O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([CH:27]=[CH:26][C:25]([OH:29])=[O:28])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: C=CC(=O)O
Reactant: CC(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: CC(=O)Nc1ccc(C=CC(=O)O)cn1
Yield: 66.2 %

Procedure:
To a mixture of N-(5-bromo-pyridin-2-yl)-acetamide (1.26 g, 5.86 mmol) and tri-n-butylamine in xylenes (10 mL) is added Pd(OAc)2 (1.4 mg, 0.006 mmol) and triphenyl phosphine (15.4 mg, 0.06 mmol). Acrylic acid (0.48 mL, 7.03 mmol) is then added dropwise over 5 minutes. The mixture is heated to reflux for 5 hours. The solution is cooled to ambient temperatures. The mixture is diluted with water and the pH is adjusted to 4 with 1N HCl. The solution is extracted with EtOAc/CH2Cl2 (2:1). The resulting suspension is filtred to give the title compound (0.80 g, 3.88 mmol) as a white solid. MS (ion spray) 207, (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].C[O-].[Na+].CO>CCOCC>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:20](=[O:21])[C:19]([F:26])([F:25])[F:18])=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C(CC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 64.4 h
Yield: 95.3 %

Procedure:
A solution of 4-benzyloxyacetophenone (6.50 g, 29 mmol) in ether (70 mL) was cooled to 0° C. and treated with ethyl trifluoroacetate (4.12 g, 29 mmol) and 25% sodium methoxide in methanol (6.39 g, 30 mmol). The reaction was warmed to room temperature and stirred for 64.4 hours. The reaction was quenched with 3 N HCl (15 mL), extracted with ethyl acetate, washed with brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow solid (8.91 g, 96%): mp 92.4-96.5° C. 1H NMR (CDCl3) 15.30 (br s, 1 H), 8.86 (d, 2 H, J=8.9 Hz), 7.43 (m, 5 H), 7.08 (d, 2 H, J=8.9 Hz), 6.50 (s, 1 H) 5.16 (s, 2 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[O:23][CH3:24])[NH:11][C:7]=2[CH:6]=1)=O.[CH3:27][NH2:28]>>[CH3:27][NH:28][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[O:23][CH3:24])[NH:11][C:7]=2[CH:6]=1)=[O:2]
Reactant: CN
Reactant: COC(=O)c1ccc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2c1
Product: CNC(=O)c1ccc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2c1
Yield: 67 %

Procedure:
One and one-half grams (4.0 mmol) of 5-methoxycarbonyl-2-(2'-methoxy-4'-methanesulfonylamino-phenyl)-benzimidazole and 10 ml of methylamine were heated for four hours to 120° C. in a steel canister. Then, excess methylamine was evaporated off, and the residue was dissolved in a small amount of water and neutralized with concentrated hydrochloric acid. After the solution was evaporated, the crude product obtained was purified by chromatography (150 gm of silica gel; eluant: methylene chloride with 10% ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:20]=[N:19][N:18]=2)[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.FC(F)(F)C(O)=O.Br[C:36]1[N:41]=[C:40]2[NH:42][C:43](=[O:46])[CH2:44][NH:45][C:39]2=[N:38][CH:37]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)(C)C.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:20]=[N:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[C:36]1[N:41]=[C:40]2[NH:42][C:43](=[O:46])[CH2:44][NH:45][C:39]2=[N:38][CH:37]=1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CNc2ncc(Br)nc2N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)NC(=O)CN2
Temperature: 100 °C
Yield: 14.6 %

Procedure:
3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (See Example 2.C) (0.465 g, 1.259 mmol), 7-bromo-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one trifluoroacetate (0.432 g, 1.259 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.103 g, 0.126 mmol), sodium carbonate (1 M in water, 3.78 mL, 3.78 mmol), 1,4-dioxane (2.5 mL) and isopropanol (1 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated at 100° C. for 70 min. The resulting mixture was diluted with water and dichloromethane and filtered through a fitted funnel. Solids were washed with 20% methanol in dichloromethane. Filtrate and wash were combined and the solvent was removed under reduced pressure. The residue was triturated with acetonitrile. Water was added. Solids were collected by vacuum filtration and washed thoroughly with water and diethyl ether. Solids were washed with 20% methanol in dichloromethane. Filtrate and wash were combined and the solvent was removed under reduced pressure. The residue was taken up in hot DMSO and methanol, filtered and purified using reverse-phase preparatory HPLC (20-65% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate and concentrated nearly to dryness under reduced pressure. Solids were collected by vacuum filtration, washed with water and dried under high vacuum to give the desired product (0.072 g, 0.184 mmol, 15% yield) as an off-white solid. MS (ESI) m/z 392.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][OH:11])[O:7]2)[O:3]1.N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][O:11][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[O:7]2)[O:3]1
Reactant: CC1(C)O[C@H]2O[C@H](CO)[C@H](O)[C@H]2O1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@H](O)[C@H]2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of 1,2-O-isopropylidene-α-D-xylofuranose 1 (30 g, 0.15 mol) in 360 mL of CH2Cl2 was cooled to 0° C. and to it was added 20 mL (0.23 mol) of pyridine and a catalytic amount (1.0 g) of N,N-dimethylaminopyridine. The resulting mixture was stirred at 0° C. for 10 min, at which time 20 mL (0.17 mol) benzoyl chloride was added to it dropwise over a period of 30 min. The reaction mixture was stirred at 0° C. for an additional 30 min and then quenched by the addition of 200 mL a saturated solution of NH4Cl. The reaction was allowed to warm to room temperature, the layers were separated, and the aqueous layer was extracted with 3×50 mL of CH2Cl2. The combined organic extracts were washed with 3×50 mL of a 10% aqueous solution of CuSO4, 2×50 mL of water and brine. The organic solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product mixture was purified by chromatography on silica gel to afford 44.3 g (95% yield) of 2 as a colorless liquid: Rf 0.54 (60% EtOAc/hexane); 1H-NMR (CDCl3) δ8.03 (m, 2H), 7.40-7.68 (m, 3H), 5.97 (d, 1H, J=3.6 Hz), 4.80 (m, 1H), 4.61 (d, 1H, J=3.4 Hz), 4.37 (m, 2H), 4.20 (s, broad, 1H), 3.35 (broad, 1H), 1.50 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CS(C)=O>[C:13]1([C:11](=[O:12])[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:3][CH:4]=2)=[O:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CCC(=O)c1ccc(F)cc1)c1ccccc1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: O=C(CCC(=O)c1ccc(N2CCCCC2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
1-(4-Fluoro-phenyl)-4-phenyl-butane-1,4-dione (390 mmol, 100 mg) and piperdine (3.9 mmol, 0.34 mL) are dissolved in DMSO (100 uL) in a vial. The vial is capped and allowed to heat/shake at 110° overnight. After which time, the reaction is checked by HPLC. After the reaction cooled to room temperature, 500 uL of water is added. The product precipitates and is filtered. 74 mg is collected and confirmed by LCMS.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:28]=1)[CH:24]=O>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:28]=1)[CH2:24][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: O=Cc1cc(Cl)cc(-c2ccccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(Cl)cc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-chloro-5-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 437.10 g/mol.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: NC1CCN(Cc2ccccc2)C1
Solvent: CCO
Product: CCOC(=O)c1cnc(NC2CCN(Cc3ccccc3)C2)[nH]c1=O
Temperature: 80 °C

Procedure:
Ethyl 2-(methylthio)-6-oxo-1,6-dihyropyrimidine-5-carboxylate (313 mg, 1.460 mmol) and 1-benzylpyrrolidin-3-amine (257 mg, 1.460 mmol) were dissolved in 10 mL of ethanol and heated at 80° C. overnight. The precipitate was not evident so the solution was heated to 90° C. overnight. The final product was then recovered.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCCC1O[CH2:20][C:21]1[CH:29]=[CH:28][C:27]([CH2:30][O:31]C2CCCCO2)=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].C(OCC)(=O)C.CCCCCC>CO>[OH:31][CH2:30][C:27]1[CH:26]=[C:22]2[C:21]([CH2:20][O:24][C:23]2=[O:25])=[CH:29][CH:28]=1
Reactant: O=C(O)c1cc(COC2CCCCO2)ccc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C1OCc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
p-Toluenesulfonic acid monohydrate (103.0 mg, 0.54 mmol) was added to a solution of 2,5-bis[(tetrahydropyran-2-yl)oxymethyl]benzoic acid (1.62 g, 4.64 mmol) obtained from Example 1-(3) in methanol (30 ml), and the mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure to afford a solid residue. This residue was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=1:1˜1:0) to give the title compound (587.5 mg, 77% yield) as a colorless solid (mp. 107-108° C.).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[C:17]2[O:16][CH2:15][CH2:14][C:13]=2[C:12]([CH2:18][CH2:19][CH2:20][NH2:21])=[CH:11][CH:10]=1.C1COCC1>N1C=CC=CC=1>[F:8][C:9]1[C:17]2[O:16][CH2:15][CH2:14][C:13]=2[C:12]([CH2:18][CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: NCCCc1ccc(F)c2c1CCO2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCCc1ccc(F)c2c1CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (0.18 ml) was added dropwise to a solution of 3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propylamine (256 mg) in, dry THF (10 ml) containing pyridine (0.21 ml) at 0° under nitrogen and the solution stirred overnight at room temperature. The solution was evaporated and the residue purified by column chromatography. Eluting with dichloromethane:methanol: (50:1) gave the title compound as a colouriess oil (133 mg)
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[CH3:14][C@H:15]1[C:20](=[O:21])[C@H:19]([CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:18]2[CH2:33][C@H:16]1[C:17]2([CH3:35])[CH3:34]>C1COCC1>[OH:13][C:9]1[CH:8]=[C:7]([C@@:20]2([OH:21])[C@H:19]([CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@@H:18]3[CH2:33][C@@H:16]([C:17]3([CH3:34])[CH3:35])[C@H:15]2[CH3:14])[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(Br)c1
Reactant: C[C@H]1C(=O)[C@H](CN(C)CCc2ccccc2)[C@@H]2C[C@H]1C2(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H]1[C@H]2C[C@@H]([C@@H](CN(C)CCc3ccccc3)[C@]1(O)c1cccc(O)c1)C2(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
Add a solution of t-BuLi (20 mL, 26.0 mmol) via syringe to a solution of 3-bromo-phenol (2.06 g, 12 mmol) in THF (20 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add a solution of (1R,2R,4S,5S)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-one (2.99 g, 10 mmol) in THF (2 mL) to the reaction mixture and stir the reaction mixture at −78° C. for additional 2 hours. Quench the reaction with saturated NH4Cl solution (30 mL). Extract the aqueous mixture with EtOAc (60 mL×3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by Preparative HPLC to give (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol as pale yellow oil (0.27 g, yield: 6.9%), MS (m/z): 394 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[OH-].[Na+]>CC(C)=O>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:14]
Reactant: O=C(Cl)c1ccco1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccco1)N1CCNCC1

Procedure:
To a solution of 21.5 g. (0.25 mol) of piperazine in a mixture of 960 ml. of acidified water (pH = 4.5) and 1200 ml. of acetone, 32.5 g. (0.25 mol) of furoyl chloride are added dropwise while the pH is maintained at 4.5 by dropwise addition of a sodium hydroxide solution. The mixture is made alkaline, and extracted several times with chloroform. The chloroform is distilled off and the concentrated extract is distilled in vacuo. 18.3 g. of the N-(2-furoyl)piperazine thus obtained in 50 ml. of diethyl ether are added to an equivalent amount of cyanogen bromide in a mixture of 60 ml. of water and 60 ml. of diethyl ether. The mixture is stirred overnight at room temperature and then subjected to continuous extraction with benzene. The extract is dried over sodium sulphate and the solvent is distilled off. According to the NMR and IR spectra the residue consists of 1-cyano-4-(2-furoyl)piperazine, m.p. 63°-65°C.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10](Br)[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[N-:33]=[N+:34]=[N-:35].[Na+].[N-]=[N+]=[N-]>O>[C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([N:33]=[N+:34]=[N-:35])[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)NC(=O)CN1C(=O)C(Br)CC(c2ccccc2)c2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)CN1C(=O)C(N=[N+]=[N-])CC(c2ccccc2)c2ccccc21
Yield: 80.1 %

Procedure:
To a 125 ml round-bottomed flask equipped with a nitrogen inlet were added 8.2 grams (18.5 mmol) N-tert-butyl 2-(3-bromo-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl) ethanoic acid amide and 40 ml dimethylformamide. After dissolution, a solution of 1.44 grams (22.2 mmol) sodium azide in 2 mL water (with two additional 0.75 ml portions of water) was added, and the solution heated at 80°-85° C. for 4 hours 20 minutes (at this point, tlc and NMR of an aliquot indicated a 75/15/10 ratio of desired azide/isomeric azide/starting material). The reaction was cooled, poured into water, and extracted twice into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 3:1 hexane/ethyl acetate to give 5.80 grams (77%) of a foam which solidified.