Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][OH:17])[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][O:17][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOc1ccccc1CO
Product: CCOc1ccccc1COc1ccncc1[N+](=O)[O-]
Yield: 65.9 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 2-ethoxybenzyl alcohol, the titled compound was obtained as a yellow solid. (Yield: 65.9%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[C:5]([O:17][CH2:18][CH3:19])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](B(CC)CC)[CH3:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([C:10](=[O:11])[CH2:9][CH2:8][C:6]2[C:5]([O:17][CH2:18][CH3:19])=[CH:4][N:3]=[C:2]([CH2:26][CH3:27])[CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCB(CC)CC
Reactant: CCOc1cnc(Cl)cc1CCC(=O)C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cnc(CC)cc1CCC(=O)C1CCCC1
Temperature: 150 °C
Yield: 67.6 %

Procedure:
A solution of 3-(2-chloro-5-ethoxy-pyridin-4-yl)-1-cyclopentyl-propan-1-one (1.2 g, 4.3 mmol) dissolved in DMF (10 mL) was treated with potassium carbonate (0.88 g, 6.4 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.11 mmol), and triethylborane (4.5 mL, 4.5 mmol). The reaction was heated to 150° C. for 2 hours. The reaction was quenched with 1 N HCl and then made basic with 2 N NaOH. The mixture was extracted with ether and the organic layers were dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the product (0.8 g, 68%). 1H NMR (300 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3H), 1.42 (t, J=6.9 Hz, 3H), 1.55-1.87 (m, 8H), 2.73 (m, 4H), 2.86 (m, 3H), 4.11 (q, J=6.9 Hz, 2H), 6.93 (s, 1H), 8.06 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:28]I>C(OCC)C>[CH3:28][O:3][CH:4]([C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CI
Reactant: CCCCCC(O)c1cccc(OCc2ccc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCC(OC)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of sodium hydride (0.5 g) in ethyl ether at 0° C. is added 2-[3-(1-hydroxyhexyl)phenoxymethyl]quinoline (1.8 g) in ether. The mixture is allowed to warm to room temperature. Methyl iodide (0.6 ml) is added and the reaction is stirred at room temperature for three days. The reaction mixture is quenched with saturated aqueous ammonium chloride and extracted with ethyl ether. The organic extract is washed with water, dried (MgSO4) and concentrated to an oil, which is purified by HPLC on silica gel using a 1:9 ratio of ethyl acetate/hexane as an eluent.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]([CH:26]([NH:28][C:29]([C:31]2[N:32]=[C:33](Cl)[O:34][CH:35]=2)=[O:30])[CH3:27])[CH:17]=[C:18]([F:25])[C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>>[F:25][C:18]1[CH:17]=[C:16]([CH:26]([NH:28][C:29]([C:31]2[N:32]=[C:33]([O:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:34][CH:35]=2)=[O:30])[CH3:27])[CH:15]=[C:14]([F:13])[C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: Oc1cccc(C2CCCC2)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(NC(=O)c1coc(Oc2cccc(C3CCCC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 71.9 %

Procedure:
3-Cyclopentylphenol (40 mg, 0.25 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted using K2CO3 (50 mg, 0.36 mmol) as described above to give the title compound (40 mg, 75%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C@H:61]1[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:60][C@H:61]3[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]3)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CC[C@H](O)CC1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (200 mg, 0.54 mmol; example 5.1) in dry DMF (4 mL) was added dry DIPEA (3.2 mmol) followed by HATU (1.6 mmol) at 0° C. Then the reaction mixture was allowed to warm to rt and stirred for 45 min at that temperature. TLC shows total consumption of acid and formation of a new spot. (trans)-4-Amino-cyclohexanol (0.64 mmol) was added to this reaction mixture at 0° C. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. TLC shows total consumption of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid and DMF was removed in vacuo at 60° C. It was then diluted with H2O (5 ml). Aqueous layer was extracted with EtOAc (5×5 mL) and combined organic layers were washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo. Crude product was subjected to column chromatography [SiO2 (230-400 mesh), EtOAc:Hexane 10:90] to give the title compound (40 mg, 24%) as off-white solid. MS: m/e=470.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[Li]CCCC.CN(C)CCN(C)C.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31]>CCOCC>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[CH:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1)[OH:31]
Reactant: O=Cc1ccccn1
Reactant: COc1cccc(CO)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a solution of 3-methoxybenzylalcohol (50.0 g, 0.36 mol) in ether (1.1 L) at -20° C. was added n-BuLi (76.0 mL, 0.756 mol) at such a rate that the internal temperature of the reaction was maintained at less than -10° C. When the addition of n-BuLi was complete, the mixture was warmed to room temperature and stirred for 2 hours. The mixture was cooled to 0° C. and tetramethylethylene diamine (42.0 g, 0.36 mol) was added. The reaction mixture was cooled to -30° C. and 2-pyridinecarboxaldehyde (58.0 g, 0.36 mol) was added over 5 minutes. The reaction was warmed to 0° C. over a 30 minute period and was then quenched with water (500 mL). The mixture was chilled for 24 hours, and the product was collected by filtration and washed with ether. The product was recrystallized from ethanol to afford 30.0 g (34%) of α-[2-(hydroxymethyl)-6-methoxyphenyl]-2-pyridinemethanol (Formula X: R2 =6-OCH3 ; R1 =H). The mother liquor from the recrystallization step was concentrated, diluted with ether and refrigerated for 16 hours. A solid precipitated, which was collected by filtration to afford an additional 13.1 g of the desired product for a total of 43.1 g (49%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[NH2:27]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:27][C:26]2[CH:28]=[C:29]([CH3:31])[CH:30]=[C:24]([CH3:23])[CH:25]=2)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(=O)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1cc(C)cc(C)c1)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Reaction time: 60 h

Procedure:
Monoimine (9,1.13 g, 3.87 mmol) and 3,5-dimethylaniline (0.5 g, 4.13 mmol) were dissolved in 25 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 60 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 0.79 g (52%) of mixed diimine (12). 1H-NMR (CDCl3) δ 8.37 (d, 1H, Py-Hm), 8.32 (d, 1H, Py-Hm), 7.87 (t, 1H, Py-Hp), 7.42 (d, 1H, ArH), 7.18 (t, 1H, ArH), 7.07 (t, 1H, ArH), 6.76 (s, 1H, ArH), 6.54 (d, 1H, ArH), 6.46 (s, 2H, ArH), 2.40 (s, 3H, Me), 2.39 (s, 3H, Me), 2.33 (s, 3H, Me), 1.36 (s, 9H, But).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(=O)c(C#N)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
To a stirred mixture containing 66 g of 5-acetyl-1,2 -dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile and 450 ml of chloroform was added dropwise over a period of about 40 minutes a solution containing 60.8 g of bromine in 50 ml of chloroform. The resulting mixture was stirred at room temperature for about 3 hours and then heated on a steam bath for 30 minutes during which time the red color of the reaction mixture disappeared. The reaction mixture was allowed to stir at room temperature for 1 hour and then filtered using a sintered glass funnel. The filtered product was washed with acetone and dried at 60° C. to yield 97.8 g of 5-(bromoacetyl)-1,2-dihyro-6-methyl-2-oxo-3-pyridinecarbonitrile, m.p. 212°-214° C. with decomposition. A 20 g portion of this product was dissolved in a boiling mixture of 400 ml of methanol and 200 ml of dimethylformamide, the hot solution treated with decolorizing charcoal and filtered and the filtrate concentrated on a rotary evaporator to remove the solvents. The residue was boiled with methanol and the white powdery solid was collected, washed with methanol and dried to yield 16.4 g of 5-(bromoacetyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, m.p. 213°-215° C. with decomposition.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:17]1[CH:21]=[C:20]([CH2:22][C:23]([NH2:25])=[S:24])[N:19]=[CH:18]1>>[NH:17]1[CH:21]=[C:20]([CH2:22][C:23]2[S:24][C:2]3[CH2:11][CH2:10][C:9]4[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=4)[C:3]=3[N:25]=2)[N:19]=[CH:18]1
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CCC1Br
Agent: Cl
Product: O=[N+]([O-])c1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1CC2

Procedure:
Starting compounds: 2-bromo-7-nitro-1-tetralone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:21]1[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21]2[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[C:4]([F:9])[CH:3]=1
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 4-bromo-2-fluorobenzenamine (0.058 g, 0.31 mmol) in THF (2 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (0.56 mL, 0.56 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. Methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.060 g, 0.28 mmol) was then added dropwise as a solution in THF (1 mL) and the reaction mixture was stirred for 25 minutes at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted with 0.1M HCl and then diluted with EtOAc and saturated NaCl and the layers separated. The aqueous layer was back extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 20:1) gave 0.086 g (84%) pure desired product as a white crystalline solid. MS ESI (+) m/z 371, 373 (M+, Br pattern) detected; 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.79 (s, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 6.58 (t, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [OH-].[K+].[CH2:3]([SH:5])[CH3:4].[CH3:6][O:7][C:8](=[O:26])[CH:9](Cl)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.C(OCC)C>CO>[CH3:6][O:7][C:8](=[O:26])[CH:9]([S:5][CH2:3][CH3:4])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CCSC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Potassium hydroxide (0.092 g; 1.64 mmole) was dissolved in methanol. Ethanethiol (0.133 g; 2.14 mmole) and 3-(4-benzyloxyphenyl)-2-chloropropanoic acid methyl ester (0.5 g; 1.64 mmole) were added. The reaction mixture was stirred at room temperature over night. Diethyl ether (15 ml) was added. The mixture was filtered and evaporated. The residue was purified by adding active charcoal in methanol. The mixture was stirred for 15 minutes and the active charcoal was filtered off. Evaporation of the solvent gave 0.47 g (86.7% yield) of 3-(4-benzyloxyphenyl)-2-ethylsulfanyl propanoic acid methyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-chlorophenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N-:8]=[N+:9]=[N-:10].[Na+]>[OH-].[Na+].C(O)C.C(Cl)(Cl)Cl>[N:8]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=Nc1ccncc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
4-Chloropyridine (400 mg) was dissolved in 2.6 ml of a 1M aqueous solution of sodium hydroxide and 1.5 ml of ethanol, 340 mg of sodium azide was added to the solution at room temperature and the mixture was stirred at 110° C. for 4 hours. The reaction solution was returned to room temperature, diluted with chloroform and washed with water and then a saturated saline solution. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo to give 140 mg of the crude product of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([Li])(CC)C.[C:15](=[O:17])=[O:16].Cl>C1COCC1.CCCCCC>[OH:6][CH:5]1[C:4]2[C:3](=[C:2]([F:1])[CH:9]=[CH:8][CH:7]=2)[C:15](=[O:16])[O:17]1
Reactant: O=Cc1cccc(F)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OC(O)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a -70° C. solution of the dimethylacetal of 3-fluorobenzaldehyde (5.3 g, 31 mmol) in THF (35 ml) was added dropwise sec-butyllithium (22.2 ml of a 1.4 M solution in hexane), and the red solution was stirred for 0.5 h. The solution was saturated with CO2 for 5 min with tne red color dissipating to yield a light yellow solution. After 10 min the reaction was allowed to warm to room temperature, and after 30 min HCl (3.5 ml) was added. After concentration the solution was made basic with 5% KOH (25 ml), the neutral material extracted with Et2O (2×40 ml), the base layer acidified to pH 1 witn HCl, and the product extracted with EtOAc (2×75 ml). Work up as usual afforded 4.5 g (86%) of the title compound, mp 11°-119°, suitable for use in the next step. Recrystallization of this material from EtOAc/PE gave analytically pure material: mp 126°-127° C.; IR 3400 (br s), 1740-1760 (structured s), 1630 (m), 1485 (m), 1300 (m), 1085 (s), 910 (m), 760 (m); 1H NMR 7.8-7.1 (highly structured m, 3 H), 6.60 (br s, 1H); exact mass calcd for C8H5O3F m/e 168.0227, obsd 168.0226.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8]>N1C=CC=CC=1>[N:1]1([CH:7]([CH3:8])[C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: C=CC(=O)OCC
Reactant: c1c[nH]nn1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)n1ccnn1
Temperature: 90 °C
Yield: 73.2 %

Procedure:
A mixture of 1,2,3-triazole (5 g, 72.4 mmol) and ethyl acrylate (7.8 ml, 72.4 mmol) containing pyridine (50 drops) was heated at 90° C. for 4 hours. After cooling, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/ether to give ethyl (1H-1,2,3-triazol-1-yl)propanoate (8.96 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:23][CH3:24])[C@@H:10]([CH3:22])[CH2:11][C:12](=[O:21])[CH2:13]4.[N:25]#CBr.C(=O)([O-])[O-].[K+].[K+]>>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@:9]2([O:23][CH3:24])[C@@H:10]([CH3:22])[CH2:11][C:12](=[O:21])[CH2:13]3)#[N:25]
Reactant: N#CBr
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3

Procedure:
A slurry of 3,14-dimethoxy-8β,17-dimethylmorphinan-6-one (35) (4.4 g, 0.0134 mol), cyanogen bromide (4.2 g, 0.04 mol), and anhydrous potassium carbonate (5.5 g, 0.04 mol) in 140 ml of methylene chlordie was heated at reflux temperature for 22 hours under a nitrogen atmosphere. The potassium carbonate was removed by suction filtration and the filter cake washed throughly with methylene chloride. The solvent was removed from the filtrate under reduced pressure to leave 4.1 g (90% theory) of the title compound which was used in the next reaction step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1)[CH3:22]
Reactant: O=C(c1ccc(F)cc1)N1CCCC1CN1CCCC1
Reactant: CCNCC
Product: CCN(CC)c1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1

Procedure:
(4-Diethylamino-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from (4-Fluoro-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and diethylamine in a manner substantially similar to Procedure A. MS (APCI+) 330 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)[C:13]2=[O:27])=[CH:4][C:5]2[CH2:10][O:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:28]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[O:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[CH2:21][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2([C:3]3=[CH:4][C:5]4[CH2:10][O:9][CH2:8][O:7][C:6]=4[CH:11]=[C:2]3[O:1][CH2:28]2)[C:13]1=[O:27]
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCOC3)c2ccccc2N1C[C@H]1CCCO1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)COCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2-g][1,3]benzodioxine-6,3′-indol]-2′(1′H)-one was obtained (3%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.38-6.99 (m, 4H), 6.47 (s, 1H), 6.30 (d, J=3.6 Hz, 1H), 5.15 (ABq, 2H), 4.89 (d, J=9.0 Hz, 1H), 4.71-4.61 (m, 3H), 4.30-4.20 (m, 1H), 3.96-3.64 (m, 4H), 2.10-1.60 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.8, 177.8, 160.5, 160.5, 153.9, 142.8, 142.7, 132.3, 132.2, 128.8 (2C), 123.6, 123.3, 122.4, 122.3, 119.6 (2C), 113.9, 109.6, 109.5, 99.2, 91.2, 80.3, 76.9, 68.2, 68.1, 66.2, 57.5 (2C), 44.7, 44.6, 29.2, 29.0, 25.6, 25.5; MS (ES+) m/z 379.9 (M+1), 401.8 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13](=[O:14])[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:19])[CH3:18])[CH3:17]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 35 °C
Yield: 40.7 %

Procedure:
To a solution of 4-chlorophenol (3 g, 23.3 mmol) in ethanol (100 mL) at room temperature is added potassium hydroxide (1.3 g, 23.3 mmol). The suspension is warmed at ˜35° C. for 15 min to complete dissolution before ethyl α-bromoisobutyrate (3.46 mL, 23.3 mmol) is introduced. The reaction is then heated to reflux where it is maintained for 16 h. After this time, the mixture is cooled to room temperature and filtered. The collected solids are washed with additional ethanol (10 mL) and the combined filtrates are concentrated under reduced pressure. The residue is dissolved in DCM (60 mL) and washed with water (×2). The organic phase is dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a clear colourless liquid (2.30 g, 40%). 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.25 (3H, t, J=7.1 Hz), 1.58 (6H, s), 4.23 (2H, q, J=7.1 Hz), 6.78 (2H, d, J=9.0 Hz), 7.19 (2H, d, J=9.1 Hz); m/z: 243/245 [M+H+].