Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10]O.[OH-].[Na+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[ClH:7].[Cl:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: ClCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
1.72 g (20.3 mmol) of piperidine, 2 ml (24.3 mmol) of 3-chloropropanol and 10 ml toluene were added successively into a reaction flask. The mixture was heated to the reflux temperature and reacted for 4 h. Into the reaction mixture, 5% NaOH 4 ml was added, and the mixture was refluxed for 1 h. After cooling to room temperature, the mixture was washed with 5% NaOH solution. The organic layer was washed with a saturated saline solution, then dried over anhydrous sodium sulfate and filtrated. 3 ml (40.6 mmol) thionyl chloride was added dropwise into the filtrate in an ice-bath, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated to dry in a reduced pressure, and the residue was recrystallized with absolute ethyl alcohol to obtain 2.4 g of a khaki solid with the yield of 59%. m.p. 218-220° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16]>ClC(Cl)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:15](=[O:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1cc([N+](=O)[O-])ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
4-Nitrophenol (1.61 g, 11.6 mmol) was dissolved in dichloroethane (10 ml) and aluminum chloride (2.31 g, 17.3 mmol) was slowly added in three portions. The addition of acetylchloride (0.818 ml, 11.51 mmol) was followed by stirring at 50° C. for 2 hours. The reaction was terminated with the addition of ice water (10 ml) and 2N hydrochloric acid solution (10 ml) at 0° C. The reaction mixture was extracted with dichloroethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give the title compound (Yield 78%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[N+]([O-])([O-])=O.[Ag+:14]>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Ag:14]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Product: [Ag]
Temperature: 40 °C

Procedure:
A silver benzotriazole emulsion was prepared by dissolving 28 grams of gelatin and 13.2 grams of benzotriazole in 300ml of water. The resulting solution was agitated at 40° C. A solution of 17 grams of silver nitrate in 100 ml of water was added to the solution over a period of 2 minutes.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.I[CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1>[CH2:24]([NH:20][C@@H:17]1[C@@H:15]2[C@@H:14]([CH2:13][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)[CH3:25]
Reactant: CCI
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Temperature: 65 °C
Reaction time: 72 h

Procedure:
(3aR,4S,6aS)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (120 mg, 0.359 mmol) from Step A of Example 256, iodoethane (0.287 mL, 3.59 mmol), and triethylamine (0.750 mL, 5.38 mmol) were in tetrahydrofuran (1 mL). The reaction was stirred at 65° C. for 3 days, and then the solvent was removed in vacuo. The residue was diluted with dichloromethane (5 mL), and addition of saturated aqueous sodium bicarbonate gave the products as a solid. This material was purified using a 12 g silica gel cartridge with a gradient of 0-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give two products. The second product was further purified on 4×0.25 mm preparative thin-layer chromatography plate eluting with 6% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.17-8.19 (m, 2H), 7.93-7.95 (m, 2H), 3.38 (dd, J=9.8, 3.1 Hz, 1H), 3.15 (dd, J=9.6, 3.2 Hz, 1H), 3.06 (dd, J=9.8, 8.0 Hz, 1H), 2.96 (dd, J=9.6, 7.7 Hz, 1H), 2.78 (q, J=6.1 Hz, 1H), 2.44-2.58 (m, 4H), 2.25-2.33 (m, 1H), 1.85-1.92 (m, 1H), 1.75-1.85 (m, 1H), 1.16-1.34 (m, 2H), 1.05 (t, J=7.1 Hz, 3H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(C)(C)C.[N:15]1C=CC=CC=1.C1(C)C=CC=CC=1>>[C:8]1([S:11]([NH2:15])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccccc1

Procedure:
Reaction with p-tert-butylbenzenesulphonyl chloride in pyridine/toluene at room temperature yielded pure 4-tert-butyl-N-[3-(2-tetrahydropyranyloxyethoxy)-2-methoxy-phenoxy)-phenyl]-benzenesulphonamide. MS: Mt /e=555.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C1COCC1>[CH2:29]([O:36][NH:37][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([F:11])[C:2]([Cl:1])=[CH:3][C:4]=1[NH:12][CH:13]1[CH2:15][CH2:14]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1NC1CC1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(Cl)cc1NC1CC1
Yield: 100.3 %

Procedure:
Following the procedure of Example A, 4-chloro-2-cyclopropylamino-5-fluoro-benzoic acid (Example C-3, 2.0 g, 8.7 mmol) was reacted with carbonyldiimidazole (1.7 g, 10.5 mmol), O-benzylhydroxylamine hydrochloride (1.67 g, 10.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) in THF (50 mL) to give 2.92 g of the title compound.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9](F)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH3:12].O>C(N)=O>[NH2:12][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([F:1])[N:10]=1
Reactant: NC(=O)c1ccc(F)nc1F
Reactant: N
Solvent: O
Solvent: NC=O
Product: NC(=O)c1ccc(N)nc1F
Reaction time: 24 h
Yield: 31 %

Procedure:
A solution of 2,6-difluoronicotinamide (4.68 g, 0.029 mmol) in dry formamide (30 mL) is saturated with ammonia and allowed to stand at room temperature for 24 h. Water (50 mL) is added and the resultant precipitate is filtered off and washed well with water, to give 6-amino-2-fluoronicotinamide (1.41 g, 31%) mp 236-237° C. 1H NMR (DMSO) δ 7.89 (1H, dd, J=10.4, 8.4 Hz), 7.31, 7.16 (1H, 1H, 2 brs,), 6.93 (2H, brs), 6.36 (1H, dd, J=8.4, 2.4 Hz).
Reaction SMILES: C(Cl)Cl.[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].[CH2:16]([B:20]([O-:22])[O-:21])[CH2:17][CH2:18][CH3:19]>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].[C:16]1([B:20]([O-:22])[O-:21])[CH:6]=[CH:5][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCB([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Solvent: O
Product: [O-]B([O-])c1ccccc1
Reaction time: 0 h

Procedure:
A solution of 100 mg/dL of glucose his phenylboronate and dry methylene chloride was prepared and applied to CLINISTIX® glucose test strip pad. No color development was observed. The pads were then wetted with water and in 2 or 3 minutes color development was observed. Glucose his butylboronate was similarly applied to CLINISTIX® strips. Again no color was observed upon application. After wetting with water strong color development was observed in 10 to 15 seconds.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[C:22]([F:28])[CH:21]=1>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][C:22]=1[F:28])=[O:3]
Reactant: OCc1ccc(Br)cc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1ccc(Br)cc1F
Product: Cl

Procedure:
4-Bromo-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was synthesized from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 4-bromo-2-fluorobenzyl alcohol according to the methods described in Examples 52 and 54 to give the product as a white solid: δH (400 MHz, DMSO-d6) 1.3 (6H, d J, 7.2 Hz), 3.0–3.2 (4H, m), 4.3 (2H, sextet, J 7.2 Hz), 5.15 (2H, s), 7.42 (2H, m), 7.6 (1H, m), 9.15 (1H, br) and 9.80 (1H, br); LC (XTERRA, 50/80, 220 nm) 89.8% (3.62 min).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[NH2:33]/[C:34](/[CH3:43])=[CH:35]\[C:36]([O:38][CH2:39][CH2:40][C:41]#[N:42])=[O:37]>CC(O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:28]2[C:35]([C:36]([O:38][CH2:39][CH2:40][C:41]#[N:42])=[O:37])=[C:34]([CH3:43])[NH:33][C:11]([CH2:10][O:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:12]2[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:30]=[CH:31][CH:32]=1
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: O=C(COCCC1CCCCC1)CC(=O)OCc1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCc2ccccc2)=C(COCCC2CCCCC2)N1
Temperature: 70 °C

Procedure:
0.50 g (1.57 mmol) of benzyl 4-(2-cyclohexylethoxy)acetoacetate, 0.22 g (1.57 mmol) of 3-chlorobenzaldehyde and 0.24 g (1.57 mmol) of 2-cyanoethyl 3-aminocrotonate were stirred in 8 ml of 2-propanol under heating at 70° C. for 22 hours. After 2-propanol was evaporated under reduced pressure, the residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/2) to obtain the title compound.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[C:10]([C:12]1([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([N:26]2[CH2:39][CH2:38][C:29]3[NH:30][C:31]4[C:32]([OH:37])=[CH:33][CH:34]=[CH:35][C:36]=4[C:28]=3[CH2:27]2)=[O:25])=[O:17])[CH2:14][CH2:13]1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]([C:12]1([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([N:26]2[CH2:39][CH2:38][C:29]3[NH:30][C:31]4[C:32]([O:37][CH2:3][CH2:4][N:5]5[CH2:9][CH2:8][CH2:7][CH2:6]5)=[CH:33][CH:34]=[CH:35][C:36]=4[C:28]=3[CH2:27]2)=[O:25])=[O:17])[CH2:14][CH2:13]1)#[N:11]
Reactant: ClCCN1CCCC1
Reactant: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(O)cccc4c3C2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(OCCN5CCCC5)cccc4c3C2)CC1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
Following on from Example 34, 1-(2-chloroethyl)pyrrolidine hydrochloride (82.0 mg, 0.48 mmol) was added to (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-hydroxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (131 mg, 0.32 mmol) and potassium carbonate (134 mg, 0.97 mmol) in DMF (5 mL) at 25° C. under air. The resulting solution was stirred at room temperature for 45 hours, to yield after purification a cream solid. (6.00 mg, 3.7%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[Cl:25])(=[O:4])=[O:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:26]([NH:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:7][C:6]=1[Cl:25])(=[O:3])=[O:4])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)c(Cl)c2)=C(c2ccccc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Cl

Procedure:
150 mg of 5-{4-(aminosulfonyl)-3-chlorophenyl}-2,2-dimethyl-4-phenyl-3(2furanone (Example 367) in 10 ml dichloromethane was reacted with 0.3 ml acetic anhydride in the presence of 0.5 ml triethylamine and 15 mg of 4-(N,N-dimethylamino)pyridine at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, which was followed by extraction with 30 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and then was purified by column chromatography (hexane/ethylacetate 2:1) to afford 113 mg of 5-[4-{(acetylamino)sulfonyl}-3-chlorophenyl]-2,2-dimethyl-4-phenyl-3(2H)-furanone as a solid. mp: 194-195° C. NMR: δ1.57 (s, 6H), 2.10 (s, 3H), 7.27 (m, 2H), 7.40 (m, 3H), 7.68 (dd, J=8.4, 1.8 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H), 8.45 (br s, 1H). IR (cm−1): 3195, 3104, 1698, 1377, 1164.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:15])[N:9]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-:37]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:37])=[O:15])[N:9]1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-((S)-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-tetrahydro-pyridazine-1,2-dicarboxylic acid di-tert-butyl ester (1.22 g, 2.5 mmol) in THF (15 mL) at 0° C., is added a solution of LiOH (7 mL, 5% in H2O). After stirring at 0° C. for 2 hours, the reaction mixture is diluted with 15 mL of water and extracted with 20 mL of ether. The ether layer is extracted with 10 mL of saturated NaHCO3. The combined aqueous layers is acidified with saturated NaHSO4 to Ph=2, and extracted with CH2Cl2 (3×20 mL). The combined organic layers is dried over Na2SO4 and concentrated to give clued product (0.83 g) as a pale gum without further purification for next step reaction. (NMR and MS data confirmed, U-3133-56-22).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]#[C:7][C:8]1([OH:19])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1)=[O:5])[CH3:2].[H][H].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1([OH:19])[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C#CC1(O)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CCOC(=O)CCC1(O)CN(C(=O)OC(C)(C)C)C1
Yield: 54.4 %

Procedure:
To palladium on carbon (10%, 75 mg) under a nitrogen atmosphere was added a solution of tert-butyl 3-(2-(ethoxycarbonyl)ethynyl)-3-hydroxyazetidine-1-carboxylate (0.20 g, 0.74 mmol) in ethanol (10 ml). The suspension was subjected to hydrogen (Parr hydrogenation apparatus) at 45 Psi for 3 hrs. The reaction was filtered and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 50% ethyl acetate/hexanes to give the title compound as a colorless oil 0.11 g, 50%. 1H NMR (CDCl3, 400 MHz) 1.28 (3H, t), 1.43 (9H, s), 2.15 (2H, t), 2.50 (2H, t), 3.32 (1H, s), 3.83 (4H, dd), 4.18 (2H, q).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH:13]C(=O)CC[C:17]([OH:19])=[O:18])=[CH:3]1.C1(CCNC(=O)CCC(O)=[O:38])C2C(=CC=CC=2)C=CC=1.[CH2:41](NC(=O)CC[C:53]([OH:55])=[O:54])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH:46]1[CH:45]=[CH:44][C:43]([CH2:42][CH:41]([OH:38])[C:17]([OH:19])=[O:18])=[CH:48][CH:47]=1.[NH2:13][C@H:12]([C:53]([OH:55])=[O:54])[CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][CH:3]=1
Reactant: O=C(O)CCC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=C(O)CCC(=O)NCCc1cccc2ccccc12
Reactant: O=C(O)CCC(=O)NCCc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)C(O)Cc1ccccc1
Reaction time: 72 h

Procedure:
An aqueous solution of DL-phenyllactic acid (Sigma-Aldrich Japan) and L-tryptophan (Wako Pure Chemical Industries, Ltd.) was prepared so that the total concentration of the compounds was 400 ppm and adjusted to pH 7 with hydrochloric acid, and the solution was subjected to an adzuki bean root promotion assay (Itagaki et al. 2003. Biological activities and structure-activity relationship of substitution compounds of N-[2-(3-indolyl)ethyl]succinamic acid and N-[2-(1-naphthyl)ethyl]succinamic acid, derived from a new category of root-promoting substance, N-(phenethyl) succinamic acid analogs. Plant Soil 255: 67-75). The base of an adzuki section was immersed in the test solution for 72 hours, and adventitious roots generated 7 days after immersion were counted. The repetition number was 5.
Reaction SMILES: CS[C:3]1[N:12]2[C:6]([CH:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.[OH-:23].[K+]>>[C:17]1([CH:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11][N:12]3[C:3](=[O:23])[NH:4][N:5]=[C:6]23)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [OH-]
Reactant: CSc1nnc2n1C=Cc1ccccc1C2c1ccccc1
Agent: [K+]
Product: O=c1[nH]nc2n1C=Cc1ccccc1C2c1ccccc1

Procedure:
3-Methylthio-11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine was treated with potassium hydroxide and the reaction mixture was treated as described. This procedure provided 2,11-dihydro-11-phenyl-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Colorless needles (as recrystallized from methanol), m.p. 258°-260° C.
Reaction SMILES: [F:1][C:2]1[C:3](O)=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21]([O-:24])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:3]([O:24][CH2:21][C:2]2[CH:3]=[CH:4][CH:7]=[CH:8][CH:9]=2)=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)c(O)c(F)c1O
Reactant: ClCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1OCc1ccccc1

Procedure:
To a 0.1M solution of Compound 13 (1.0 eq) in acetone is added benzyl chloride (4.0 eq) and anhydrous K2CO3 (7.0 eq). The mixture is heated to reflux for 8 hours and filtered. The filtrate is concentrated in vacuo, and the residue is dissolved in EtOAc. The resulting solution is washed with 3% HCl, washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue is recrystallized from MeOH to yield Compound 23.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O.[F:20][C:21]([F:29])([F:28])[C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25]>C(O)(=O)C.S(=O)(=O)(O)O>[F:20][C:21]([F:29])([F:28])[C:22]([C:23]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:24]=1[CH3:25])=[O:27]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(=O)C(F)(F)F)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 28.4 %

Procedure:
To a stirred solution of 50 mg (0.18 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone in 2 ml acetic acid was added 0.022 ml (0.18 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 20 mg (28%) 2,2,2-trifluoro-1-[4-(4-methoxy-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a white solid. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O.[CH2:12]([NH:19][C:20]([NH2:22])=[S:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([NH:19][C:20]1[S:21][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[N:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=S)NCc1ccccc1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Solvent: CCO
Product: c1ccc(CNc2nc(-c3ccccn3)cs2)cc1

Procedure:
A solution of 2-(Bromoacetyl)pyridine hydrobromide (100 mg, 0.36 mmol) in ethanol (2 mL) was treated with 1-benzyl-2-thiourea (90 mg, 0.54 mmol). The resulting yellow solution was concentrated, and the crude residue was purified on reverse phase HPLC to produce N-benzyl-4-(pyridin-2-yl)thiazol-2-amine.
Reaction SMILES: [Ca:1].O.O.O.O.[N+]([O-])([O-])=[O:7].[Ca+2].[N+]([O-])([O-])=O.[P].[P:16](=[O:20])([OH:19])([OH:18])[OH:17].OO>C(O)C.O>[P:16]([O-:20])([O-:19])([O-:18])=[O:17].[Ca+2:1].[Ca+2:1].[Ca+2:1].[P:16]([O-:20])([O-:19])([O-:18])=[O:17].[O-2:7].[Ca+2:1]
Reactant: O=P(O)(O)O
Reactant: [Ca]
Reactant: O=[N+]([O-])[O-]
Agent: OO
Agent: [Ca+2]
Agent: [P]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])[O-]
Product: [O-2]

Procedure:
A Calcium solution was made by dissolving 115.05 g of Calcium Nitrate tetra hydrate in 250 ml of ethanol. A phosphorus solution was made by adding 20 ml of 85% w/w aqueous Phosphoric acid to 50 ml of 30% w/w aqueous Hydrogen peroxide. The resulting solutions were mixed, adding the Calcium solution to the Phosphorus slowly with constant vigorous stirring. No precipitates were formed during or on the immediate mixing of the two solutions but subsequent to achieving the correct Ca/P ratio (complete mixing) turbidity did develop, the composition containing dispersed colloidal gelatinous material. This composition was feed to the inner venturi of a coaxial combustion nozzle. Air was supplied in the outer venturi and a pilot flame provided the means to ignite the atomised composition. The combustion products were directed into a stainless steel vessel containing water. After burning a powdered material was recovered form the water dried overnight at 100° C. and submitted for XRD (X-Ray Diffraction) analysis. The resulting XRD pattern is shown in FIG. 4. As indicated the burning of the ethanol/aqueous solution having a molar Calcium to Phosphorous ratio of 1.67 resulted in the formation of crystalline HAP without further high temperature processing Furthermore none of the peaks characteristic of TriCalcium Phosphate (TCP) and Calcium Oxide (CaO) are observed in the diffraction pattern demonstrating the advantage of the hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8](Cl)=[CH:7][CH:6]=1.C([O-])(=[O:18])C.[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](=[O:18])[NH:9][N:10]=1
Reactant: CC(=O)[O-]
Reactant: Fc1ccccc1Cc1ccc(Cl)nn1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(Cc2ccccc2F)n[nH]1
Temperature: 110 °C
Yield: 65.6 %

Procedure:
6-(2-Fluorobenzyl)-3-chloropyridazine (2.5 g, 11.2 mmol) [prepared as described above] was dissolved in acetic acid (15 ml). Sodium acetate (3.37 g, 24.8 mmol) was added and the reaction mixture was heated at 110° C. under a nitrogen atmosphere. After 1.5 h the reaction mixture was diluted with water and the product was extracted into ethyl acetate. The organic extracts were washed with water, aqueous NaHCO3 and brine, and dried over MgSO4. The solvent was removed in vacuo and the crude product was chromatographed on a silica gel column (50% ethyl acetate in hexanes) to give 6-(2-fluorobenzyl)-2H-pyridazin-3-one (1.5 g, 55% yield) as a yellow solid.