Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[C:22]3[N:23]([C:27]([Br:31])=[C:28]([CH3:30])[N:29]=3)[CH:24]=[CH:25][CH:26]=2)[CH3:15])=[O:13])=[O:9])=[CH:4][CH:3]=1.[C:39]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40]1>O1CCOCC1>[Br:31][C:27]1[N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH2:19][C:18]3[C:32]([Cl:35])=[CH:33][CH:34]=[C:16]([N:14]([C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:45])[CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:38][CH:37]=4)[CH3:15])[C:17]=3[Cl:36])[C:22]2=[N:29][C:28]=1[CH3:30]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)cc4)c3Cl)cccn2c1Br
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCC(=O)O)cc4)c3Cl)cccn2c1Br
Yield: 100.4 %

Procedure:
A solution of 8-[3-[N-(4-aminocinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (150 mg) and succinic anhydride (26 mg) in dioxane (3 ml) was refluxed for 2 hours. After cooling, the solution was removed in vacuo to give 3-bromo-8-[3-[N-[4-(3-carboxypropionamido)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (175 mg) as amorphous.
Reaction SMILES: [C:1]1([Li])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12.[Cl-:18].[Cl-].[Cl-].[CH:21]1([Zr+3:26])[CH:25]=[CH:24][CH:23]=[CH:22]1>C1(C)C=CC=CC=1.C(OCC)C>[Cl-:18].[Cl-:18].[C:1]1([Zr+2:26][CH:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12
Reactant: [Zr+3]C1C=CC=C1
Reactant: [Li]c1cccc2c1C=C1C2=Nc2ccccc21
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C1=CC([Zr+2]c2cccc3c2C=C2C3=Nc3ccccc32)C=C1
Reaction time: 8 h

Procedure:
A sample of the indeno[1,2-b]indolyl lithium salt produced above (10 g, 42 mmol) is dissolved in toluene (95 mL) to produce an orange slurry. Diethyl ether (35 mL) is added slowly to give an orange solution. This solution is added over 15 min. at room temperature with stirring to a slurry of cyclopentadienylzirconium trichloride (11 g, 42 mmol) in toluene (190 mL) and diethyl ether (190 mL). The mixture turns deep red and is kept at room temperature overnight. The slurry is filtered to recover a red solid, which is washed with toluene (200 mL) and dried under vacuum to give the catalyst (16.5 g, 78%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C@H:5]1[C:23](=[O:24])[O:22][C@H:7]2[CH2:8][C@:9]3([CH3:21])[O:11][C@H:10]3[C@@H:12]3[O:14][C@@H:13]3[C:15]3[C:19](=[O:20])[O:18][C@@H:17]([C@H:6]12)[CH:16]=3>CC(C)=O>[CH3:1][N:2]([CH3:3])[CH:13]1[C:15]2=[CH:16][CH:17]([O:18][C:19]2=[O:20])[CH:6]2[CH:7]([O:22][C:23](=[O:24])[CH:5]2[CH3:4])[CH2:8][C:9]2([CH3:21])[CH:10]([O:11]2)[CH:12]1[OH:14]
Reactant: C[C@H]1C(=O)O[C@H]2C[C@]3(C)O[C@H]3[C@@H]3O[C@@H]3C3=C[C@@H](OC3=O)[C@@H]21
Reactant: CNC
Solvent: CC(C)=O
Product: CC1C(=O)OC2CC3(C)OC3C(O)C(N(C)C)C3=CC(OC3=O)C21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of dimethylamine (500 μmol, 250 μl, 2M in THF) is added to a solution of dihydromikanolide (100 μmol, 29 mg) in acetone (1 ml). The reaction mass is stirred for 2 hours at ambient temperature then the solvent is eliminated by evaporation under reduced pressure. The residue is taken up in ether, filtered and dried under vacuum. 25 mg of product is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)[O:17][N:16]=1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[O:17][N:16]=1
Reactant: COC(=O)Cc1cccc(OCc2cc(OCc3nc(-c4ccccc4)oc3C)no2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2cccc(CC(=O)O)c2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetate (604 mg) was dissolved in methanol-tetrahydrofuran (1:1, 12 mL) and a 1N aqueous sodium hydroxide solution (3 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, 1N hydrochloric acid (3 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethloxy]phenyl]acetic acid. Recrystallization from ethanol-hexane gave colorless needle crystals (522 mg, 89%). melting point: 128-129° C.
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[C:6]([CH2:20][CH:21]=[CH2:22])[CH:5]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:26])=O>CN(C)C=O.C(Cl)Cl>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:26])=[O:15])=[C:6]([CH2:20][CH:21]=[CH2:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCc1cc(C(C)=O)c(O)cc1OCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3.06 g of 6-(4-acetyl-5-hydroxy-2-allylphenoxy)hexanoic acid, 1.74 ml of oxalyl chloride, 100 ml of methylene chloride, and ten drops of dimethylformamide was mixed at 0° C. and allowed to warm to room temperature. After stirring for 4 hours, the solvents were removed by evaporation to provide the desired title product. NMR.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12](S(C)(=O)=O)=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][OH:30]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]([O:30][CH2:29][C:28]4[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=4)=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: OCc1cccc(F)c1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3c(c2)CCO3)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Yield: 48 %

Procedure:
A solution of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole (0.15 g, 0.56 mmol), potassium carbonate (111 mg, 0.80 mmol) and 3-fluorobenzyl alcohol (91 μL, 0.83 mmol) in N,N-dimethylformamide (5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=3/1) and recrystallized from hexane/ethyl acetate to give the title compound (84 mg, yield 48%) as colorless crystals.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:13]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]([P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[O:13])=[CH:16][CH:17]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(OC(=O)Cl)cc1
Product: CCOP(=O)(OCC)C(=O)Oc1ccc(OC)cc1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
18.6 g (0.12 mole) of triethylphosphite was heated at 125°-130° in a flask with a reflux condensor. 18.6 g (0.10 mole) of 4-methoxyphenyl chloroformate (prepared according to M. J. Zabik and R. D. Schuetz, J. Org. Chem. 32 (1967) 300) was added dropwise. The reaction flask was heated additionally at about 120° for 11/2 hours and left at room temperature overnight. The product was distilled to give 25.8 g (89%) of diethyl 4-methoxyphenoxycarbonylphosphonate. B.p.0.03 174°-8°, nD21 1.4940. Analysis for C12H17O6P. Found (calculated): C 49.79 (50.00), H 6.01 (5.95), P 10.54 (10.75). NMR (CDCl3)δ: 1.42 (t, CH3), 3.78 (s, OCH3), 4.13-4.63 (CH2), 6.77-7.33 (aromatic). IR (neat) cm-1 : 1740 (CO), 1275, 1255, 1190, 1030.
Reaction SMILES: [CH2:1]([O:5][P:6]([C:13]1[CH:17]=[C:16](I)[S:15][CH:14]=1)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:19]([O:23][P:24]([C:31]1[CH:35]=[C:34]([Sn](CCCC)(CCCC)CCCC)[S:33][CH:32]=1)([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:20][CH2:21][CH3:22].[Cu]C#N.[F-].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:5][P:6]([C:13]1[CH:17]=[C:16]([C:34]2[S:33][CH:32]=[C:31]([P:24]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH:35]=2)[S:15][CH:14]=1)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOP(=O)(OCCCC)c1csc(I)c1
Reactant: CCCCOP(=O)(OCCCC)c1csc([Sn](CCCC)(CCCC)CCCC)c1
Agent: N#C[Cu]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(OCCCC)c1csc(-c2cc(P(=O)(OCCCC)OCCCC)cs2)c1
Yield: 80 %

Procedure:
At room temperature, 0.0804 g (0.2 mmols) of 3-(dibutoxyphosphoryl)-5-iodothiophene and 0.0092 g (0.008 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in 2 ml of toluene, to which 0.1131 g (0.2 mmols) of 3-(dibutoxyphosphoryl)-5-(tributylstannyl)-thiophene and 0.0036 g (0.04 mmols) of commercially available copper(I) cyanide were added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 2 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 1 hour. Thereafter, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=1:2 and ethyl acetate:hexane=1:1) to obtain the specified substance in the form of a white solid at a yield of 0.0881 g (yield: 80%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Br[CH:13]([CH3:17])[C:14](=O)[CH3:15].C(#N)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:13]([CH3:17])=[C:14]([CH3:15])[N:11]=2)[CH:5]=[C:6]([C:7]([NH2:9])=[O:8])[CH:10]=1
Reactant: CC(=O)C(C)Br
Reactant: NC(=O)c1cnc(N)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
5,6-Diaminonicotinamide (12.5 g, 82 mmol), 3-bromo-2-butanon (13.6, 90 mmol) and acetonitrile (150 ml) were refluxed for 20 h. Additional 3-bromo-2-butanon (4.0 g, 26.5 mmol) was added and the reaction mixture was refluxed for 5 h. Upon cooling the solids were removed by filtration. The solids were added to methylene chloride (150 ml), methanol (150 ml) and potassium carbonate (22 g, 160 mmol) and were stirred for 30 min. The solids were removed by filtration and evaporation of the solvents under reduced pressure gave an oily residue. Purification by column chromatography on silica gel eluting with methylene chloride:methanol (5:1) gave 3.3 g (20%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl.N([O-])=O.[Na+].[N-:17]=[N+:18]=[N-].[Na+]>O>[N:8]([C:7]1[CH:9]=[CH:10][C:4]([O:3][CH:2]([F:11])[F:1])=[CH:5][CH:6]=1)=[N+:17]=[N-:18]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(OC(F)F)cc1
Temperature: 0 °C

Procedure:
In a 20 mL four-necked flask, 4-(difluoromethoxy)aniline (0.5 g, 3.14 mmol) and hydrochloric acid (37% in water, 0.54 ml, 6.6 mmol) were combined with water (5 ml) to give a light yellow solution. Cooled to 0° C. using an ice-bath, sodium nitrite (217 mg, 3.14 mmol) was dissolved in water (1 ml) and added carefully ensuring that the temperature did not increase above 5° C. Sodium azide (204 mg, 3.14 mmol) was dissolved in water (1 ml) and added drop-wise to the orange solution, keeping the temperature below 5° C. The reaction mixture was cooled at 0-5° C. for 1 hour and an orange emulsion was observed. The layers were separated using TBME and the organic layer was washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated under vacuum to yield 1-azido-4-(difluoromethoxy)benzene as an orange liquid.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21]Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K]>CN(C=O)C>[CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][N:27]3[C:23](=[O:33])[C:24]4[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:26]3=[O:28])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(NC1CCCCC1)c1ccc(CBr)c2ccccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Temperature: 100 °C
Yield: 36 %

Procedure:
To a solution of 4-bromomethyl-naphthalene-1-sulfonic acid cyclohexylamide 41 (150 mg, 0.39 mmol) in DMF (5 mL) was added potassium phthalimide (109 mg, 0.58 mmol). The resultant solution was stirred at room temperature and then heated to 100° C. for 3 hr. The reaction was quenched with water and extracted with CH2Cl2. The organic layers were dried and concentrated in vacuo. HPLC purification of the residue gave the title compound (G-4) (63 mg) as white foam. 1H NMR (300 MHz, MeOD) δ 8.67 (d, 1H), 8.42 (d, 1H), 8.22 (d, 1H), 7.88 (m, 23H), 7.76 (m, 4H), 5.48 (s, 2H), 4.48 (d, 1H), 3.12 (d, 1H), 1.58 (m, 6H), 1.10 (m, 4H); LC/MS m/z 449 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1([CH3:19])[CH2:18][O:17]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[OH-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:17])([CH3:19])[CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: CC1(c2ccc(Oc3ccc(Cl)cc3)cc2Cl)CO1
Reactant: c1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 110 °C

Procedure:
A mixture of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-methyloxirane (109 g), 1,2,4-triazole (27 g) and sodium hydroxide (16 g) in NMP (1 L) was heated to 110° C. for 1 h. The reaction mixture was then partitioned between MTBE and aq. NaHCO3 solution and the aq. phase was extracted twice with MTBE. The combined organic phases were washed with water (2×), dried and evaporated. The crude product was crystallized from diisopropyl ether.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].OO.C(C1C=CC=CC=1)(=[O:18])C>>[O:1]([C:2]([C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3])[OH:18]
Reactant: CC(=O)c1cccc(C(C)(C)O)c1
Reactant: CC(=O)c1ccccc1
Agent: OO
Product: CC(=O)c1cccc(C(C)(C)OO)c1

Procedure:
A process for producing m-hydroxyacetophenone which comprises reacting m-(2-hydroxy-2-propyl)acetophenone with 1 to 20 moles of 5 to 90% by weight aqueous hydrogen peroxide solution per mole of said acetophenone at 30° to 95° C. in the presence of a mineral acid catalyst to form m-(2-hydroperoxy-2-propyl)acetophenone, and then decomposing the m-(2-hydroperoxy-2-propyl)acetophenone by warming with sulfuric acid, hydrochloric acid, perchloric acid, boron trifluoride, sulfuric acid anhydride or toluenesulfonic acid to form m-hydroxyacetophenone.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]([C:18]([F:21])([F:20])[F:19])=[C:7]([C:22]([F:25])([F:24])[F:23])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:16][C:15]1[N:11]([C:10]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([C:22]([F:25])([F:23])[F:24])=[C:8]([C:18]([F:19])([F:20])[F:21])[CH:9]=2)[C:12]([CH3:17])=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.28 g, 3.49 mmol) in methanol (25 ml) was added 1M NaOH (7 ml, 6.99 mmol) and the reaction mixture was left to stir at RT for 30 min. The solvent was removed in vacuo and water (20 ml) was added to the remaining residue. The pH was adjusted to pH 4/5 by the addition of 1M HCl. The mixture was extracted with EtOAc (3×20 ml) and the combined organic extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo and dried in a vacuum oven (50° C.) overnight to give the crude title product as an orange solid which was used without further purification; LC-MS: Rt 1.23 min; MS m/z 353.1 [M+H]+; Method 2 minLC_v003.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[H-].[Na+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CN(C=O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([O:12][CH:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][N:2]([CH3:1])[CH2:11]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1Cc2ccccc2C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2ccccc2C(Oc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,2,3,4-tetrahydro-2-methyl-4-isoquinolinol (3.0 g, 0.018 mole) in dry DMF (15 ml) is added dropwise under nitrogen to a suspension of sodium hydride 50% (98%) (1.1 g, 0.022 mole), previously washed with hexane, in dry DMF (25 ml). The mixture is warmed to 60° C., at which time a solution of 4-fluorobenzonitrile (2.2 g, 0.018 mole) in dry DMF (15 ml) is slowly added. The reaction mixture is stirred at room temperature for 16 hours.
Reaction SMILES: C(OC(=O)N[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[N:13]=2)[CH2:9]1)(C)(C)C.Cl.N1CCC1>>[N:10]1([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[N:13]=2)[CH2:11][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccnc(Cl)n2)C1
Agent: C1CNC1
Agent: Cl
Product: Clc1nccc(N2CCC2)n1

Procedure:
Prepared as [1-(2-chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester using azetidine hydrochloride. MS: [M+H]+=170
Reaction SMILES: [OH-].[Na+:2].[ClH:3].[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7]>O>[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].[Cl-:3].[Na+:2]
Reactant: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [Cl-]
Reaction time: 2 h
Yield: 2.5 %

Procedure:
In another formulation, 8 g of HPC (63.7 mmol of hydroxyl groups) dissolved in 100 g of water was heated with 2.23 g (55.8 mmol) of sodium hydroxide and 1 g (3.27 mmol) of TSTMP. Heating was carried out in a sealed glass reactor at 110° C. for 2 h. After cooling, the unreacted sodium hydroxide was neutralized using about 20 mL of 4 M hydrochloric acid, to yield a dispersion of crosslinked HPC microspheres with a weight-average particle diameter of about 4.3 μm. The viscosity of the dispersion was about 31.2 cP. A 20% (w/v) dextrose solution (120 mL) was then added to obtain a formulation with 10% (w/v) dextrose, 3.3% (w/v) HPC, about 2.5% (w/v) sodium chloride. The dispersion was heated at 60° C. for 10 min after sugar addition. The weight-average particle diameter in the final dispersion was about 4.5 μm, and the dispersion viscosity was about 31 cP. The dispersion viscosity was sensitive to the order in which the solutions were mixed. If the dextrose solution was added after the second heating step (60° C. for 10 min), the viscosity of the resulting dispersion was higher (about 55 cP).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C[O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([OH:33])=[O:23])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: c1coc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4ccco4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.8 g (10 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-indole and 2.5 g (11 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up, 1.5 g (36% of yield) of the expected acid were obtained.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)[C:8]2[CH:9]=[CH:10][C:11]([OH:19])=[C:12]([CH:18]=2)[C:13]([O:15]CC)=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Li+].[OH-].Cl>C1COCC1>[CH:1]1([CH2:6][N:7]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:25][CH:26]=2)[C:8]2[CH:9]=[CH:10][C:11]([OH:19])=[C:12]([CH:18]=2)[C:13]([OH:15])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(N(Cc2ccc(C#Cc3ccc(OC)cc3)cc2)CC2CCCC2)ccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccc(CN(CC3CCCC3)c3ccc(O)c(C(=O)O)c3)cc2)cc1
Temperature: 100 °C
Yield: 114.9 %

Procedure:
To a solution of ethyl 5-((cyclopentylmethyl){4-[(4-methoxyphenyl)ethynyl]-benzyl}amino)-2-hydroxybenzoate (200 mg; 0.43 mmol) was dissolved in THF (4 mL) and water (1.00 mL) was added LiOH (178 mg; 4.26 mmol). The mixture was then heated in MW for 2500 s at 100° C. It was poured into a 1N solution of HCl and extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 225 mg of a yellow oil. The oil was suspended in methanol and triturated to give 140 mg (72%) of the title compound as a yellow powder. Rt: 4.08 min (purity: 99.1%), LC/MS: M+(ESI): 456.0, M−(ESI): 454.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1(=O)O[CH2:15][CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:15][CH2:14][OH:13])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Oc1cccc2cnccc12
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc2cnccc12
Temperature: 155 °C
Yield: 67.5 %

Procedure:
A mixture of 5-hydroxyisoquinoline (2.05 g, 14.1 mmol), ethylene carbonate (1.43 g, 16.2 mmol), K2CO3 (0.97 g, 7.1 mmol) in DMF (6 mL) was heated at 155° C. for 1.5 h under stirring in a sealed tube. After cooling, the mixture was diluted with CHCl13 and filtered through a pad of Celite. The brownish filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel using EtOAc as eluent to give 1.8 g (67%) of the title product as a beige oil which solidified on standing: mp 64-67° C.; HRMS m/z calcd for C11H11NO2 (M)+ 189.0790, found 189.0789. Anal. (C11H11NO2) C, H, N.