Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (1.7 g, 7.4 mmol) and Et3N (1.12 g, 11.1 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1 g, 8.87 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was washed with brine. The organic layer was concentrated in vacuo to give crude tert-butyl 4-(2-(methylsulfonyloxy)ethyl)piperazine-1-carboxylate (2.1 g, 94%). This was used in the next step without purification. 1H NMR (300 MHz, CDCl3): δ 4.38 (t, 2H, J=5.3 Hz), 3.49-3.44 (m, 4 h), 3.09 (s, 3H), 2.79 (t, 2H, J=5.1 Hz), 2.58 (t, 4 h, J=5.0 Hz), 1.49 (s, 9H). LCMS: No molecular ion observed for desired mass.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30]>>[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:27][CH2:28][C:29](=[O:30])[C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH2:20][CH2:19]2)[CH:13]=1)=[O:10]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCl)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3cccs3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(2-thienyl)-1-butanone: ESMS m/e: 399.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])=[N:4][CH:3]=1.[NH3:19]>CO>[Br:1][C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])=[N:4][CH:3]=1
Reactant: CCCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Reactant: N
Solvent: CO
Product: CCCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of methyl 5-bromo-2-(3-propylureido)isonicotinate (Intermediate 42, 128 g, 405 mmol) and 7N ammonia in methanol (1 L) was allowed to stir at room temperature for 3 d. Stirring for the reaction was then stopped and the solids were allowed to settle. The precipitated was then vacuum filtered, rinsed with methanol (2×500 mL), and then dried on the high vacuum pump overnight, yielding 123 g (quant) of 5-bromo-2-(3-propylureido)isonicotinamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]#[N:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].[N-:31]=[N+:32]=[N-:33].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[NH:31]1[C:27]([CH2:26][C@H:10]2[CH2:9][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11]2=[O:25])=[N:28][N:33]=[N:32]1
Reactant: N#CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1[C@@H](Cc2nnn[nH]2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Temperature: 90 °C
Reaction time: 96 h

Procedure:
To a solution of 136 mg (0.33 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetonitrile (Example 55, Step A) in 1.8 mL of DMF was added ammonium chloride (176 mg, 3290 μmol) and sodium azide (214 mg, 3290 μmol). The resulting mixture was stirred at 90° C. for 4 days. Then, the reaction was acidified (aq. 10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Separation by reversed phase HPLC (60-90% AcCN/H2O in 30 min) provided the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.C(O)C.O>O1CCCC1>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(CCS(=O)(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)CCc3ccc(C(=O)O)cc3)ccc21
Reaction time: 4 h
Yield: 87.7 %

Procedure:
The methyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulphonyl)-ethyl]benzoate (3.54, 8.54 mmol) is placed in solution in 256 ml of tetrahydrofuran, 25.6 ml of ethanol and 12.8 ml of water in a round-bottomed flask. 3.54 g of lithia monohydrate are added. The whole mixture is stirred for 4 hours at reflux. Ambient the reaction medium is concentrated by half, taken up with ethyl acetate and water and then brought to pH6 with 2N HCl. After extraction, the organic phase is washed with a saturated NaCl solution, dried over MgSO4, concentrated and washed with ether. 3 g of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulphonyl)ethyl]benzoic acid are obtained in the form of a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[CH2:10]O)=[CH:2]1.P(Br)(Br)Br.C([O:19][CH2:20][CH3:21])(=O)C>>[S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[CH2:10][C:4]2[CH:5]=[C:21]([CH:7]=[CH:6][CH:3]=2)[CH:20]=[O:19])=[CH:2]1
Reactant: OC/C=C/C=C/c1ccsc1
Reactant: CCOC(C)=O
Agent: BrP(Br)Br
Product: O=Cc1cccc(C/C=C/C=C/c2ccsc2)c1
Reaction time: 1 h

Procedure:
20 mg of the resulting alcohol compound was dissolved in 1.5 ml of ethyl acetate, and under ice cooling, an ethyl acetate solution (0.5 ml) of 16.2 mg of phosphorus tribromide was added dropwise. The mixture was stirred for 1 hour, and then the solvent was evaporated. The residue was dissolved in 3 ml of toluene, and under a nitrogen atmosphere, 59 mg of 3-(tributylstannyl)benzaldehyde and 3 mg of tetrakis(triphenylphosphine)palladium were added. After the mixture was refluxed for 3 hours, 1 ml of a saturated aqueous solution of potassium fluoride was added, and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added, and the organic layer separated was worked up in a customary manner. The product was purified by medium-pressure liquid chromatography [hexane/ethyl acetate=8/1] to give 7 mg of (E,E)-3-[5-(3-thienyl)-2,4-penta-dienyl]benzaldehyde as a pale yellow oil.
Reaction SMILES: C1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][N:15]1[C:19]([OH:20])=[C:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:17]([CH3:31])=[N:16]1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>CCOCC>[CH3:14][N:15]1[C:19]([O:20][C:34](=[O:35])[CH2:33][Cl:32])=[C:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:17]([CH3:31])=[N:16]1
Reactant: O=C(Cl)CCl
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1nn(C)c(OC(=O)CCl)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 82 %

Procedure:
In a mixture of 10 ml. of benzene and 0.2 ml. of triethylamine is dissolved 0.285 g. of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole and then a solution of 0.18 g. of chloroacetylchloride in 5 ml. of benzene is added dropwise under ice-cooling and stirring. After completion of the dropwise addition, the resulting mixture is stirred at room temperature for 2 hours. After completion of the reaction, ether is added to the reaction mixture and the mixture is then washed successively with 3 portions of 50 ml. of water and dried over anhydrous sodium sulfate. Then, the solvent is distilled off from the mixture and the resulting residue is recrystallized from n-hexane to give 0.297 g. of the desired product as white crystals melting at 120°-122° C. Yield 82.0%.
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:10](=[O:14])[CH2:11][O:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7])C.Cl.NO>CO>[CH3:13][O:12][CH2:11][C:10]1[O:14][N:2]=[CH:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCC(=O)C(=CN(C)C)C(=O)OC
Agent: Cl
Agent: NO
Solvent: CO
Product: COCc1oncc1C(=O)OC
Yield: 80.9 %

Procedure:
To a solution of methyl 2-[(dimethylamino)methylene]-4-methoxy-3-oxobutanoate (Preparation 43, 5.2 g, 26 mmol) in methanol (55 ml) was added hydroxylamine hydrochloride (1.8 g, 25.8 mmol) and the reaction stirred at reflux for 7 hours. The reaction was concentrated in vacuo. The solid residue was purified by trituration with ethyl acetate to afford the title compound as a solid (3.6 g, 18% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][C:5]2([CH3:13])[CH3:12].CS(O)(=O)=O.[N-:19]=[N+]=[N-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:19][CH2:6][C:5]2([CH3:13])[CH3:12]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CC(=O)c2ccc(Br)cc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CNC(=O)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (1.6 g, 6.7 mmol) was dissolved in DCM (12 mL) and cooled to 0° C. Then MeSO3H (1.83 ml, 28.1 mmol) was added, followed by the portion-wise addition of NaN3 (653 mg, 10.1 mmol) over ˜10 min, while maintaining the internal reaction temperature below 5° C. The reaction was allowed to warm to room temperature and was stirred 3 h under nitrogen. At completion, the reaction was cooled to 0° C. and quenched with 8 M aq. NaOH. After stirring 30 minutes at room temperature, the quenched reaction was partitioned between DCM (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. 6-bromo-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (711 mg, 40% yield) was isolated as a white solid after purification by flash chromatography over silica gel (eluting in 50-100% EtOAc/hexane). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (br. s., 1H), 7.77 (d, J=8.0 Hz, 1H), 7.46-7.64 (m, 2H), 3.16 (d, J=3.0 Hz, 2H), 1.27 (s, 6H); MS (EI) m/z=255.1 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6].[C:19](OC(=O)C)(=[O:21])C>C(O)=O>[CH:19]([NH:1][CH2:2][C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH2:5][OH:6])=[O:21]
Reactant: NCC(CCO)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCC(CCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In formic acid (100 ml) was dissolved 4-amino-3,3-diphenylbutanol (reference compound 7-1) (17.1 g) followed by addition of acetic anhydride (16 ml) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated to dryness and the residue was distributed between chloroform and water. The aqueous layer was made basic with aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was dissolved in ethanol (50 ml) and the solution was stirred with 1N-sodium hydroxide solution (60 ml) at room temperature for 15 minutes. To this reaction mixture was added water and the resulting crystals were recovered by filtration. The crystals were washed serially with water and ethyl acetate to provide the title compound (16 g) as colorless powder.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:57])[C@H:41]([CH2:53][CH:54]([CH3:56])[CH3:55])[NH:42]C(OCC1C=CC=CC=1)=O)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.CO.O1CCOCC1.[Pd]>[CH2:1]([C@H:8]([NH:39][C:40](=[O:57])[C@H:41]([CH2:53][CH:54]([CH3:55])[CH3:56])[NH2:42])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C)C(C)(C)C
Yield: 100.2 %

Procedure:
A solution of Example 167A (40 mg, 0.051 mmol) in ethyl acetate (0.25 mL) and methanol (0.25 mL) was treated with 1N HCl in dioxane, a hydrogen balloon, and 10% Pd/C (11 mg, 0.01 mmol) at 25° C. for 16h. The mixture was filtered, rinsed with methanol, and the solvents were evaporated to give the title compound (33 mg, 100%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1.[CH:30](=[O:32])[CH3:31]>C1COCC1>[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][C:23]=1[CH:30]([OH:32])[CH3:31]
Reactant: CC=O
Reactant: COc1ccc(-c2ccncc2)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nnc(-c2ccncc2)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution of 0.93 g 2,2,6,6-tetramethylpiperidine in 30 ml THF is added 4.13 ml (15% solution in toluene) n-butyllithium at −30° C. After being stirred at 0° C. for 30 min, the reaction mixture is cooled to −78° C. and a solution of 1.12 g 3-methoxy-6-pyridin-4-yl-pyridazine in 30 ml THF is added and stirred at −78° C. for 30 min. At this temperature, 3.17 g acetaldehyde are added and stirred for another 2 h. The reaction is quenched by the addition of 24 ml MeOH/THF 1:1 and warmed to ambient temperature. Then, 30 ml saturated aq. NaHCO3 are added and extracted with CH2Cl2. The combined organic layers are washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (ethyl acetate 100%) to give 0.91 g (66%) of the desired product as a beige solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:17]2[C:21]([CH:22]([CH3:24])[CH3:23])=[N:20][CH:19]=[N:18]2)[CH:5]=1.[OH-].[Na+].Cl>CO>[CH:22]([C:21]1[N:17]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=3)[CH:7]=2)[C:3]([OH:25])=[O:2])[N:18]=[CH:19][N:20]=1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2ncnc2C(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3ncnc3C(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 126.7 %

Procedure:
3-(5-Isopropyl-[1,2,4]triazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (2.0 g, 6 mmol) was dissolved in 30 mL MeOH, and 2.0 mL of 3N aqueous NaOH was added. The reaction mixture was stirred at room temperature for 18 hours, then cooled and acidified with 10% aqueous HCl, and concentrated under reduced pressure to yield 2.45 g of 3-(5-isopropyl-[1,2,4]triazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[O:12][CH2:11]1)[CH:2]1[O:4][CH2:3]1.[K].[CH2:14]([OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([O:22][CH2:11][CH:10]([OH:12])[CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]([CH2:3][O:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCO
Reactant: C(COCC1CO1)OCC1CO1
Agent: [K]
Product: CCCCCCCCOCC(O)COCCOCC(O)COCCCCCCCC
Yield: 49 %

Procedure:
One part of ethylene glycol diglycidyl ether and 15 parts of octyl alcohol were reacted at 60° C. for 20 hours in the presence of 0.05 parts of potassium. Purification by distillation provided 1,8-bis(octyloxymethyl)-3,6-dioxaoctane-1,8-diol (boiling point 150° C./0.03 Torr) of the following formula: ##STR8## in a yield of 49%. This compound was then added to a greatly excess amount of a mixture of chlorosulfonic acid and acetic acid and reacted at room temperature for 3 hours. The resulting product was neutralized with sodium carbonate and extracted with n-butyl alcohol, obtaining a compound of the following formula: ##STR9## in a yield of 90%. This was a viscous liquid having a purity of 80% as measured by the modified Epton method which is a method for the quantitative measurement of anionic active agents.
Reaction SMILES: [Cl-].[Li+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].N12CCCN=C1CCCCC2.[CH3:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:29]=1)=O>CC#N.CCOC(C)=O>[C:36]1([CH2:35][O:34][C:30]2[CH:29]=[C:28](/[C:26](/[CH3:25])=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[CH:33]=[CH:32][CH:31]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)/C=C(\C)c1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a suspension of lithium chloride (0.28 g, 6.6 mmol) in MeCN (9 mL) were added trimethyl phosphonoacetate (0.76 mL, 5.3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.79 mL, 5.3 mmol), and 3-benzyloxyacetophenone (available from Aldrich) (1.00 g, 4.4 mmol). The mixture was stirred overnight at reflux (100° C.), cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated. The crude product was chromatographed on silica gel (0-10% EtOAc/hexane) to afford 5.6 (0.45 g, 36%) as a colorless oil.
Reaction SMILES: [Al].O.[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[C:26]2[CH:25]=[CH:24][S:23][C:22]=2[C:21]([CH:27]=[C:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:20][CH:19]=1>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[C:26]2[CH:25]=[CH:24][S:23][C:22]=2[C:21]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:20][CH:19]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)c2sccc12
Agent: [Al]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Temperature: 50 °C

Procedure:
10 g activated aluminium needles and 1 ml water are added to a solution of 2.03 g (4.3 mmol) 5-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethylidene}-thiazolidine-2,4-dione (Fp. 204-207° C.) in 130 ml tetrahydrofuran. Then it is heated for 50 min. while stirring to 50° C. and the solid components are removed by filtration. The filtrate is evaporated and the residue is chromatographed on silica gel with a mixture of 88 parts by volume toluene, 10 parts by volume 2-butanone and 2 parts by volume glacial acetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:11][CH2:10]2)=O)=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:13]3[N:12]([CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:9]=2)=[CH:5][CH:6]=1
Reactant: O=C(c1ccncc1)C1CC1
Reactant: c1c[nH]cn1
Product: c1cc(-c2ccncc2)c2nccn2c1

Procedure:
Combine 15 g (0.10 mol) of cyclopropyl 4-pyridinyl ketone with 30 g (0.44 mol) of imidazole and heat to 180°-200° C. for 24 hr. Isolation from 200 g silica gel using 5% methanol/methylene chloride followed by crystallization from ether provides the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([Cl:16])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)Cl)c1ccc(Cl)cc1

Procedure:
2-(4-Chlorophenyl)-2-methylpropanoic acid (3.85 g, 19.4 mmol) in toluene (5 mL) and thionyl chloride (5.00 g, 3.1 mL) was heated at 80° C. for 2 hours. The mixture was cooled and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:47][CH2:48][CH:49]1[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]1>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:47][CH2:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOc1nc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
To a solution of 4-amino-5-cyano-6-ethoxypicolinic acid (193 mg) in dichloromethane (4 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (215 mg), 1-hydroxybenzotriazole hydrate (164 mg), and diisopropylethylamine (813 μL). The mixture was stirred at room temperature for 5 minutes and then tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (200 mg) was added. The reaction mixture was stirred at room temperature for 16 hours. The organic phase was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to obtain the title compound (252 mg) having the following physical data.