Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:10]=[C:11]([C:16]3[NH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12](=[O:15])[NH:13][N:14]=2)=[CH:4][C:3]=1[CH3:25].[Br:26]N1C(=O)CCC1=O>CC(C)=O>[Br:26][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[C:11]1[C:12](=[O:15])[NH:13][N:14]=[C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[C:3]([CH3:25])[CH:4]=2)[CH:10]=1
Reactant: Cc1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cc(C)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)=O
Product: Cc1cc(-c2cc(-c3[nH]c4ccccc4c3Br)c(=O)[nH]n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
10 mg of 6-(4-hydroxy-3,5-dimethyl-phenyl)-4-(1H-indol-2-yl)-2H-pyridazin-3-one is dissolved in 400 μl of acetone and 5.3 mg of N-bromosuccinimide is added. The solution is stirred at RT for 20 min and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 4 mg. LC-MS (ES+) 409/411 (M)+.
Reaction SMILES: Cl.[OH:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:4]1([CH3:21])[CH3:20].[O-:22][C:23]#[N:24].[K+].[O-]C#N>O.CO>[C:23]([O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:4]1([CH3:21])[CH3:20])(=[O:22])[NH2:24]
Reactant: N#C[O-]
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
A solution of 6.7 ml of 12 N HCl in 10 ml of water is added dropwise over 10 minutes with cooling below 0° C. to a suspension of 20.8 g (75 mmol) of 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 75 ml of methanol, and 25 ml of water in a nitrogen atmosphere. A clear solution resulted. A solution of 6.1 g (75 mmol) of potassium cyanate in 25 ml of water is added dropwise over 30 minutes. The reaction temperature is maintained at 0-5° C. during the cyanate addition. The reaction mixture is stirred 30 minutes at ambient temperature, then filtered. The precipitate is washed with water, then dissolved in 200 ml of toluene. Residual water is removed by azeotropic distillation. The toluene solution is then cooled to yield 19.4 g (81%) of a white crystalline solid, m.p. 148-49° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:18]([Cl:19])=[C:17]([Cl:20])[C:10]2[S:11][C:12]([CH:14]([OH:16])[CH3:15])=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+]>C(O)C>[Cl:19][C:18]1[C:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH:14]([OH:16])[CH3:15])[S:11][C:10]=2[C:17]=1[Cl:20]
Reactant: CCOC(=O)COc1cc2cc(C(C)O)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Yield: 77.5 %

Procedure:
To 16 g of ethyl[ (6,7-dichloro-2-(1-hydroxyethyl)benzo[b]thien-5-yl)oxy]acetate in 300 ml 95% ethanol is added 300 ml of a 6 N sodium hydroxide and the mixture is refluxed at 100° for 30 mins. The cooled mixture is concentrated to a white slurry which is diluted with 200 ml of ice-water and 200 ml of ethyl ether. With stirring and efficient cooling, the mixture is acidified with 6 N hydrochloric acid. The acidic mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the crude product from acetone and hexane gives 11.4 g of [(6,7-dichloro-2-(1-hydroxyethyl)benzo[b]thien-5-yl)oxy]acetic acid, mp 173°-175°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:16])[CH2:18][CH2:19][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCI)c1ccc(F)cc1
Reactant: CNCC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CCCC(=O)c1ccc(F)cc1)CC1CCN(Cc2ccccc2)CC1
Yield: 77 %

Procedure:
Following the procedure of step F of Example 3, starting from 1-benzyl-4-(methylaminomethyl)piperidine and 1-iodo-3-[(p-fluorophenyl)carbonyl]propane, in the presence of potassium carbonate and in acetone as solvent, the desired compound is obtained in the form of an oil, in a yield of 77%.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][CH:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14]O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([N:22](CC)CC)C.O>CS(C)=O>[CH2:16]([C:13]1[N:12]=[C:3]2[C:2]([NH2:22])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]2[CH:14]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CC(C)CC(CO)Nc1nc2ccccc2nc1Cl
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Cc1cn2c(n1)c(N)nc1ccccc12
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of the 2-(3-chloroquinoxalin-2-ylamino)-4-methylpentan-1-ol (1.90 g, 6.79 mmol) in 10 mL of DMSO was added triethyl amine (1.92 g, 19.0 mmol) and followed by sulfur trioxide pyridine complex (2.38 g, 14.9 mmol) at room temperature. The reaction mixture was stirred at that temperature overnight. And then 100 mL of water was added to reaction mixture. The resulting mixture was extracted with ethyl acetate (75 mL×2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (1.25 g, 64%). MS: MH+=278:280=3:1
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[CH2:19][CH:18]([N:21]([CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH2:17][CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O1CCOCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[CH2:19][CH:18]([N:21]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:39][CH:40]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:17][CH2:16]3)=[CH:41][CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2cccc(OCc3ccc(C(C)(C)C)cc3)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)c1ccc(COc2cccc3c2CC(N(CCCCC(=O)O)Cc2ccc(C(=O)O)cc2)CC3)cc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
68.5 mg (0.12 mmol) of the compound from Example 5A were dissolved in 0.5 ml of methanol and 1 ml of dioxane, 0.15 ml of 45% strength aqueous sodium hydroxide solution and 0.2 ml of water were added and the mixture was then stirred at a bath temperature of 100° C. for 45 min. The milky suspension was then diluted with water, acidified with 2 N hydrochloric acid and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (method 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH:12](C1C=CC=CC=1O)(C)C>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)c1ccccc1O
Reactant: CC(C)c1cc(N)ccc1O
Product: CC(C)(C)c1cc(N)ccc1O

Procedure:
4-amino-2-t-butylphenol was prepared by the procedure described in the preparation of 4-Amino-2-isopropyl-phenol substituting 2-tert. butylphenol for 2-isopropylphenol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:6]1[O:10][N:9]=[C:8]([NH2:11])[CH:7]=1)([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:22]>C1COCC1>[F:13][C:2]([F:1])([F:12])[C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)no1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (123 mg, 0.63 mmol) in THF (2 mL) was treated with potassium carbonate (113 mg, 0.819 mmol) and p-chlorophenyl chloroformate (180 mg, 0.95 mmol). The reaction mixture was stirred at rt overnight. The mixture was filtered through a celite pad, washed with ethyl acetate and concentrated to dryness. The residue was taken into ethyl acetate, washed with brine, and the organics dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 8:2) to give 4-chlorophenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (85 mg, 39%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.83 (brs, 1H), 7.38 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 6.82 (s, 1H), 1.59 (s, 6H); LC-MS (ESI) m/z 349 (M+H)+.
Reaction SMILES: N[C:2](N)=[S:3].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[F:14])CBr.Cl>C(O)C.[OH-].[Na+]>[F:5][C:6]1[CH:7]=[C:8]([CH2:2][SH:3])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: NC(N)=S
Reactant: Fc1ccc(CBr)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(CS)cc1F
Temperature: 25 °C

Procedure:
Thiourea (5.0 g) was added to a solution of 3,4-difluorobenzyl bromide (13.6 g) in ethanol (100 ml). The mixture was heated at reflux for 3 h before removal of the volatiles in vacuo. The crude solid was suspended in aqueous sodium hydroxide solution (1.6M, 110 ml) and heated at reflux for 3 h before allowing to cool to room temperature. The reaction was acidified with concentrated hydrochloric acid and the organics extracted with ether (200 ml). The organic layer was washed with saturated sodium bicarbonate solution (2×50 ml), brine (20 ml), dried (MgSO4), and concentrated in vacuo to provide the subtitle product as a colourless oil. Yield 11.1 g
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([NH:13]C(=O)OC(C)(C)C)[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6])#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:13][C@H:4]([CH2:3][C:1]#[N:2])[C:5]([NH:7][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H](CC#N)C(=O)NC1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC[C@@H](N)C(=O)NC1CCCC1
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of (R)-tert-butyl 3-cyano-1-(cyclopentylamino)-1-oxopropan-2-ylcarbamate and 50% TFA/DCM (10 mL) was stirred for 1 h. Following reaction, the mixture was concentrated to afford the title compound as a clear oil (TFA salt, 0.265 g, 41%). The product was pure by TLC (visualized by ninhydrin stain).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4](=[O:29])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8][N:7]1C(OCC1C=CC=CC=1)=O)[CH3:2].[ClH:32].CO>CO.[Pd]>[ClH:32].[ClH:32].[CH2:30]([N:3]([CH2:1][CH3:2])[C:4](=[O:29])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8][NH:7]1)[CH3:31]
Reactant: CCN(CC)C(=O)CC1c2cc([N+](=O)[O-])ccc2CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN(CC)C(=O)CC1NCCc2ccc(N)cc21
Reaction time: 1 h

Procedure:
To a pressure bottle charged with N,N-diethyl-2-(phenylmethoxy)carbonyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-1-acetamide (10 mmols) dissolved in methanol (150 ml) and saturated methanol-HCl (20 ml) was added 10% Pd-C (250 mg), and the reaction was hydrogenated for 1 h. The catalyst was removed by filtration and the solvent evaporated to yield N,N-diethyl-7-amino-1,2,3,4-tetrahydroisoquinolin-1-acetamide dihydrochloride which was used as such in the next step.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15][C:14]=1N)=[O:12])[CH3:9]>[Cu](Cl)Cl.[Cl-].[NH4+]>[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15][CH:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Product: CCOC(=O)c1csc(-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
Anhydrous copper (II) chloride (4 g, 0.03 mol) and tert-butyl nitrite (1.9 mL, 0.019 mol) were dissolved in IMS (100 mL) then treated with 2-amino-5-phenyl-thiophene-3-carboxylic acid ethyl ester (2 g, 8.097 mmol). After 30 minutes saturated aqueous ammonium chloride (20 mL) was added and the mixture left for a further 30 minutes. The resultant precipitate was filtered off and the filtrate was concentrated, washed with DCM, dried and concentrated to give a dark oil which was purified by column chromatography, eluting with 0-35% tert-butyl methyl ether in cyclohexane to afford 5-phenyl-thiophene-3-carboxylic acid ethyl ester as a yellow oil (1.38 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].[Cl-].[NH4+]>C(O)C.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1cccc(N)c1
Yield: 85.5 %

Procedure:
(3-Nitro)phenyl methyl sulphone (prepared as described in Step 1 above) (5.396 g) reduced iron (7.5 g) and ammonium chloride (7.18 g) were mixed together in ethanol/water (2:1) (150 ml) and heated under reflux for 2 hours. The black solution was filtered through `Celite` and the pad washed with ethyl acetate. The solvents were removed under reduced pressure and the residue taken up in ethyl acetate/water. The organic layer was separated and the aqueous layer extracted with 3 further portions of ethyl acetate. The combined organic layers were washed with brine and the solvent removed under reduced pressure to give a dark orange oil (3.9275 g). This was chromatographed on silica gel using ethyl acetate-hexane (45:55 to 50:50) as eluant to give the title compound as an orange oil, yield 3.607 g.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[NH:32][C:33]3[CH:39]=[C:38]([C:40]#[N:41])[CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:27][CH2:26]1>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:26][CH2:27][CH:28]([C:31]5[NH:32][C:33]6[CH:39]=[C:38]([C:40]#[N:41])[CH:37]=[CH:36][C:34]=6[N:35]=5)[CH2:29][CH2:30]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: N#Cc1ccc2nc(C3CCNCC3)[nH]c2c1
Agent: Cl
Product: N#Cc1ccc2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Yield: 78.1 %

Procedure:
150 mg (0.5 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde described in example 1 and 136 mg (0.6 mmol) 2-piperidine-4-yl-3H-benzimidazole-5-carbonitrile hydrochloride salt were reacted and purified as described in example 6.0. 199 mg of the desired compound were obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[S:18])[CH:13]=[CH:14][CH:15]=1)#[N:9].[C:19]([O:23][C:24](=[O:27])[CH2:25][NH2:26])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:26][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[S:18])[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1cccc(N=C=S)c1
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNC(=S)Nc1cccc(C#N)c1
Temperature: 20 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
2.8 cm3 (20 mmol) of triethylamine and 3.2 g (20 mmol) of 3-cyanophenyl isothiocyanate are added at 0° C. to a solution of 3.35 g (20 mmol) of glycine t-butyl ester in 150 cm3 of dichloromethane. The mixture is stirred at 20° C. for 12 hours before being concentrated under vacuum and then taken up with a mixture of water and ethyl ether (300:300). The ether phase is separated off and washed with a 1N hydrogen chloride solution (200 cm3), and then with a saturated sodium chloride solution. After drying with magnesium sulfate and concentration under vacuum, 5.17 g (89% yield) of a yellow solid is obtained, whose melting point is 131°-132° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].O>CS(C)=O>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][C:19]2([O:22][CH2:4]2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Oil free sodium hydride (2.16 g, 0.09 M) was added to dry dimethyl sulfoxide (250 mL) under nitrogen gas and the mixture was heated to 60-65° C. until a uniform black solution was formed, about 1 h. Then 19.83 g (0.09 M) of trimethylsulfoxonium iodide was added (slight exotherm) and the mixture was stirred until a brown solution occurred, about 30 min. Then a solution of 13.40 g (67.3 mM) of N-t-butyloxycarbonyl-4-piperidone in 50 mL of dimethyl sulfoxide was stirred at room temperature for 1 h. The reaction mixture was then poured into 1 L of cold water and the whole was extracted 4× with 100 mL portions of hexane. The combined hexane extracts was back-washed with 50 mL of water and with brine solution and was dried with magnesium sulfate, filtered and evaporated to give 11.75 g of white crystalline product, 6-t-butyloxycarbonyl-1-oxa-6-azaspiro[2.5]octane, (78% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([CH:15]=[CH2:16])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1nc(Br)cc(N)c1OC
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1cc(N)c(OC)c(C(=O)OC)n1
Yield: 33 %

Procedure:
Methyl 4-amino-6-bromo-3-methoxypicolinate (1 g, 3.83 mmol), tributyl(vinyl)stannane (1.822 g, 5.75 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.403 g, 0.575 mmol) in DCE (12.77 ml) were stirred at 70° C. overnight. The mixture was adsorbed onto celite and purified by flash column chromatography (ISCO, SiO2 40 g, hexane/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-amino-3-methoxy-6-vinylpicolinate (263 mg, 1.263 mmol, 33% yield) as a yellow oil. EIMS m/z 208; 1H NMR (400 MHz, CDCl3) δ 6.86 (s, 1H), 6.71 (dd, J=17.6, 10.9 Hz, 1H), 5.98 (dd, J=17.6, 1.0 Hz, 1H), 5.42 (dd, J=10.9, 1.0 Hz, 1H), 4.45 (s, 2H), 3.97 (s, 3H), 3.87 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.94, 152.06, 148.02, 143.34, 141.60, 136.73, 118.02, 108.63, 61.49, 52.84.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[NH:7]1[C:15]2[C:10]3[C:11](=[CH:16][CH:17]=[CH:18][C:9]=3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2.C(Br)C#C.C(O)(=O)C>CN(C)C=O>[CH2:3]([N:7]1[C:15]2[C:10]3[C:11](=[CH:16][CH:17]=[CH:18][C:9]=3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2)[C:2]#[CH:1]
Reactant: O=C1Nc2cccc3cccc1c23
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C#CCN1C(=O)c2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Potassium-t-butoxide, 6.17 g (0.055 mol) was added to a solution of 8.46 g (5 mmol) of benz[cd]indol-2(1H)-one in 100 ml of dimethylformamide. After stirring for 10 minutes at room temperature, 4.9 ml (0.055 mol) of propargyl bromide was added and the mixture was stirred for 1 hour at room temperature. The reaction mixture was acidified with acetic acid and partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was dried and evaporated and the residue was crystallized from tetrahydrofuran/ethanol to leave 8 g (77%) of product with m.p. 183°-186° C. The title compound was recrystallized for analysis twice from methylene chloride/ethyl acetate and had m.p. 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]([O:8]C)=[O:7].COC1C=C(C=CC=1C)C(OC)=O.N1CCCC1.[OH-].[Na+].[ClH:39]>C(O)C>[ClH:39].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(CN2CCCC2)c(OC)c1
Agent: COC(=O)c1ccc(C)c(OC)c1
Agent: Cl
Agent: [Na+]
Solvent: C1CCNC1
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1CN1CCCC1
Reaction time: 72 h
Yield: 99 %

Procedure:
Methyl 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoate (prepared by bromination of methyl 3-methoxy-4-methyl-benzoate by the procedure of Example 1, Part A, followed by treatment with pyrrolidine) (11.56 g, 46.4 mmol), was combined with sodium hydroxide (3.71 g 92.7 mmol, 2.00 eq.) in absolute ethanol (95 mL). After 72 h, the reaction mixture was made acidic to pH 1 by the addition of conc. HCl. The solvent was removed under reduced pressure to give the corresponding acid hydrochloride as a white solid (17.92 g, 99%).
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+]([C:43]1[CH:44]=[C:45]([C:51]#[N:52])[C:46](=[CH:49][CH:50]=1)[C:47]#[N:48])([O-])=O.Cl>C1(C)C=CC=CC=1.CS(C)=O>[C:51](#[N:52])[C:45]1[C:46](=[CH:49][CH:50]=[CH:43][CH:44]=1)[C:47]#[N:48]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: N#Cc1ccccc1C#N
Temperature: 175 °C
Yield: 261.5 %

Procedure:
To a 2000 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added bisphenol-A (100 g, 438 mmol), 4,4′-dichlorobenzophenone (38.5 g, 153 mmol), powdered anhydrous K2CO3 (90.0 g, 632 mmol), toluene (25 mL), and dimethylsulfoxide (DMSO) (500 mL). Toluene was used to control the refluxing azeotropic removal of water and to control the temperature of the reaction content. The resulting mixture was degassed with nitrogen at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 170-180° C. under a nitrogen atmosphere for 6 h or until no more water was observed being collected in the Dean-Stark trap. The toluene was then slowly distilled off causing the temperature to rise in the reaction vessel to enhance the yield of the intermediate hydroxyl salt and high conversion to this intermediate. The reaction mixture was heated above 180° C. for an additional 12 h with a very small amount of toluene present to control the temperature, to totally remove the water, formed as a by-product, so that the reaction could be pushed to completion and high conversion to the hydroxyl salt intermediate. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (99.1 g, 573 mmol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 h. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile (192 g, 97% yield). IR [cm−1]: ν 3077 (C═CH), 2232 (CN), 1586 (C═C), 1478 (aromatic), 1306 (aromatic), 1308 (C—O), 1245 (CH3), 1162 (C—O), 929 (C—O), 847 (aromatic).