Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[O:15])[C:5]#[N:6].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@:24]([OH:39])([C@H:31]([S:33][CH:34]([CH2:37]O)[CH2:35][OH:36])[CH3:32])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C@H:14]2[O:36][CH2:35][C@H:34]([S:33][C@H:31]([CH3:32])[C@:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])([OH:39])[CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[CH2:37][O:15]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A mixture of 4.63 g (23.0 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile [produced as described in Step 1(ii) above], 8.73 g (24.3 mmol of (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [produced as described in Japanese Patent Application (Kokai) Hei 8-333350)], 5.07 g (26.7 mmol) of p-toluenesulfonic acid monohydrate and 200 ml of anhydrous tetrahydrofuran was allowed to stand at ambient temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated using a rotary evaporator and dried in vacuo. The resulting residue was dissolved in 150 ml of anhydrous tetrahydrofuran and the resulting mixture was then evaporated to dryness in vacuo using a rotary evaporator. This procedure was repeated twice more. A solution of the resulting residue in 150 ml of anhydrous tetrahydrofuran was poured into a saturated aqueous sodium hydrogen carbonate solution with stirring. The product was then extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residual oil was purified by chromatography on a silica gel (500 g) column using a 2:1 mixture of ethyl acetate and hexane as the eluant to give 9.35 g (yield 74%) of the title compound as a yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.CN(C)[CH:19]=[O:20]>O1CCCC1.CCCCCC.O>[CH:19]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1)=[O:20]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C=O)ccc1C(=O)O
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (10 g) in tetrahydrofuran (100 mL), a solution of 1.6M n-butyl lithium in hexane (60 mL) was added at −70° C. After the reaction mixture was stirred for one hour at −40° C., a solution of N,N-dimethylformamide (10 mL) in tetrahydrofuran (10 mL) was added to the mixture at −70° C. After stirred for one hour at −70° C. and then warmed to room temperature, the mixture was poured onto ice and diluted with water. The aqueous layer was washed with hexane and acidified with concentrated hydrochloric acid, and the precipitate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 4-formyl-2-methylbenzoic acid (5 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CN.Cl.[BH3-][C:19]#[N:20].[Na+]>CO.CC(O)=O>[CH3:19][NH:20][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 55 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.126 mmol, 1.0 eq.) was dissolved in MeOH (50 ml); AcOH (2 drops) and CH3NH2.HCl (2.2 g, 32.663 mmol, 1.3 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (3.11 g, 50.25 mmol, 2.0 eq.) was added in portions at 0° C. and the mixture was stirred for 14 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Alox, 3% MeOH in DCM). Yield: 55% (3.0 g, 14.019 mmol)
Reaction SMILES: CO.[Na].[C:4]([O:12]C)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15].Cl>C1(C)C(C)=CC=CC=1>[C:17]1([C:14](=[O:16])[CH2:15][C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
Methanol (0.26 ml, 6.4 mmol) and sodium (0.14 g, 6.1 mmol) were combined in xylene (60 ml) and stirred for 20 min at room temperature. Methyl benzoate (49, 2.47 ml, 19.7 mmol) and acetophenone (0.58 ml, 5.0 mmol) were added and the mixture stirred for 6 hr at 140° C. The mixture was cooled to room temperature and hydrochloric acid (10 ml, 6 N) was added and stirred for 15 min. The resulting mixture was extracted into ethyl acetate, washed twice with water, twice with saturated sodium bicarbonate and twice with water. The ethyl acetate was dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was chromatographed on silica gel with ethyl acetate/hexane to give a solid. The solid was recrystallized from methanol to give 0.71 g (63%) of a pink-orange solid: mp 70-71° C. [expected mp 77-78° C.]; 1H NMR: δ 6.85 (s, 1H), 7.51 (m, 6H), 7.98 (d, 4H, J=6.8 Hz); 13C NMR: δ 93.1, 127.1, 128.6, 132.4, 135.5, 185.6.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:7]1[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(Cl)Cl.O>CCCCCCCC>[CH2:12]([C:11]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC(O)(CCCCCCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCCCCCCC
Solvent: O
Product: CCCCCCCCC1(CCCCCCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (9.38 mL) was added dropwise to 9-([2,2′-bithiophen]-3-yl)heptadecan-9-ol (IIe) (6.20 g, 15 mmol) in 200 ml n-octane under stirring at room temperature. After stirring for 12 h, CH2Cl2 (130 mL) and water (130 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Ie) (3.19 g, 52.9%). 1H-NMR (CDCl3): δ=7.14 (d, J=4.8 Hz, 2H), 6.93 (d, J=5.1 Hz, 2H), 1.87-1.79 (m, 4H), 1.40-1.06 (m, 24H), 0.95-0.82 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1.[C:35]([OH:42])(=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39]>C1COCC1.C(OC)(C)(C)C.O>[OH2:8].[OH2:39].[C:35]([OH:42])(=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:8][CH2:7][CH2:6][CH2:5][NH:4][CH3:3])=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1
Reactant: CNCCCO
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Agent: O=C(O)CCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2N[C@@H](C)C(F)(F)F)c(F)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (40.9 g, 1.02 mol, 60% in oil) in anhydrous THF (750 mL) is added 3-methylamino-propan-1-ol (115 g, 1.21 mol) at about 20-30° C. dropwise over 30 min. The mixture is stirred for 30 min. Then, a solution of [5-chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-((1S)-2,2,2-trifluoro-1-methyl-ethyl)-amine (150 g, 0.379 mol) in THF (150 mL) is added slowly over 15 min. The mixture is heated to 60° C. and stirred for 16 h, then cooled to 0-6° C. Cold water (1500 mL) is added dropwise while maintain the temperature between 10±3° C. THF is removed by distillation. The reaction mixture is extracted with t-butylmethyl ether (TBME, 2×1000 mL) and to the separated aqueous phase is added in portions succinic acid (296 g, 2.51 mol) is added in portions and followed by addition of TBME (1000 mL). The mixture is cooled to 3±3° C. and stirred for 1 h. The crude solid product is filtered, washed with cold water (150 mL) and TBME (2×400 mL). The wet solid is dissolved into water (2000 mL) at about 75° C. The solution is filtered at 60-70° C. and cooled to 0° C. over 1 h and stirred for 1 h at this temperature. The solid is filtered and dried at 35° C./10 mmHg for 20 h to give a white solid in anhydrous form (175 g, 80%, >99% HPLC area purity and 99% ee). A small portion of the anhydrous compound is placed in a drying dish of 80%-100% relative humidity at about 20° C. to about 30° C. for 24 h. It absorbed 5.8% wt of water and stopped. This dihydrate is stable at about 20° C. to about 30° C. and at 5%-100% relative humidity. 1H NMR (CDCl3): δ 10.2 (bs, 1H), 8.26 (s, 1H), 6.80 (d, 2H, J=10.5 Hz), 5.79 (m, 1H), 4.13 (t, 2H, J=6.3 Hz), 3.03 (t, 2H, J=7.2 Hz), 2.57 (s, 3H), 2.35 (s, 4H), 2.07 (m, 2H), 1.27 (d, J=6.0, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.O.NN>CCO.[Pd]>[N:9]1[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:17]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cc2cccnc2c2ncccc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
This compound was synthesized by the reduction of 5-nitro-1,10-phenanthroline. The procedure was manipulated under argon. To a suspension of 5-nitro-1,10-phenanthroline (2.06 g, 9.0 mmol) and 10% Pd/C (0.280 g) in 90 ml of 95% EtOH, hydrazine hydrate (2.0 ml, 42 mmol) was added dropwise. The mixture was heated for 3 h at 70° C. and then filtered hot through a glass-fiber filter to remove the catalyst. The yellow solution was concentrated to 25 ml and left at 4° C. for 24 hours. The precipitate was filtered off, washed with cold Et2O, and dried under vacuum for 24 hours to give 1.425 g of product (81%). 1H-NMR (DMSO-d6): δ=9.08 (m, 1H), 8.71 (m, 2H), 8.06 (m, 1H), 7.75 (q, 1H), 7.52 (q, 1H), 6.90 (s, 1H), 6.17 ppm (d, NH2). 13C-NMR (DMSO-d6): δ=149.3, 146.2, 144.8, 142.7, 140.5, 132.7, 130.8, 123.2, 122.0, 101.8 ppm.
Reaction SMILES: CC(NC(C)C)C.C([Li])CCC.CCCCCC.[F:19][C:20]([F:34])([F:33])[C:21]([NH:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([O:31][CH3:32])=[O:30])=[O:22].[Br:35]CCBr>C1COCC1>[Br:35][C:27]1[S:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[C:24]([NH:23][C:21](=[O:22])[C:20]([F:19])([F:33])[F:34])[CH:28]=1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: BrCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a stirred mixture of N-(1-methylethyl)propan-2-amine (40.0 mL, 285 mmol) and THF (400 mL) at −78° C. was added slowly 1.6 M n-butyllithium in hexane (165 mL, 264 mmol). The mixture was allowed to 0° C. over 2 h. Then, the mixture was cooled to −78° C. again. Then, a solution of methyl 3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (20.3 g, 80 mmol) in THF (80 mL) was added to the mixture slowly. After 1 h, 1,2-dibromoethane (41.2 mL, 476 mmol) was added at once. The stirring was continued at −78° C. for 1 h, and the dry ice-acetone bath was removed. After further stirring for 30 min, the mixture was poured into saturated aqueous NaHCO3 (1 L) and EtOAc (1 L). After shaking well, the organic layer was collected, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. This residue was purified by column chromatography (Purif, silica gel, hexane to 90:10 hexane/EtOAc) to afford the title compound (10.4 g, 39%) as a beige solid:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(Br)c(N)c1
Yield: 51 %

Procedure:
Dissolve 4-bromo-3-nitro-benzoic acid methyl ester (4.25 g, 16.3 mmol) in ethanol (100 ml) and water (30 ml). Add sodium dithionite (15 g, 75 mmol) in a single portion and heat the mixture under reflux for 4 h. Evaporate ethanol and add water. Basify the aqueous layer with 10% sodium carbonate solution. Extract the product with EtOAc (×2). Dry the combined organic layers over anhydrous sodium sulfate, filter and concentrate to yield 3-amino-4-bromo-benzoic acid methyl ester (51%).
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[NH2:12][NH2:13].O=C(CC)CC(OC)=O>C(O)(=O)C>[NH2:5][C:4]1[CH:3]=[C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:13][N:12]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NN
Agent: CCC(=O)CC(=O)OC
Solvent: CC(=O)O
Product: Nc1cc(-c2ccccc2)[nH]n1

Procedure:
4.9 g (30.8 mmol) 3-amino-5-phenylpyrazole, which was prepared from 3-oxo-3-phenylpropionitrile and hydrazine (M. H. Elnagdi, M. R. H. Elmoghayar, G. E. H. Elgemeie, Synthesis 1984, 1), and 4.0 g (30.7 mmol) methyl 3-oxovalerate were heated for 70 min in 10 ml acetic acid. The title compound precipitated in colorless needles from the mixture upon cooling, which were filtered by suction, washed with water, and recrystallized from ethanol, m.p. 316°-318° C.
Reaction SMILES: O[C:2]1C=C[C:5]([C:8]([C:11]2[CH:16]=CC(O)=CC=2)(C)C)=[CH:4][CH:3]=1.[NH2:18]C1C=CC=CC=1.[CH2:25]=[O:26]>C1(C)C=CC=CC=1>[O:26]1[C:25]2[CH:2]=[CH:3][CH:4]=[CH:5][C:8]=2[CH2:11][CH2:16][NH:18]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Nc1ccccc1
Reactant: C=O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCNO2
Temperature: 65 °C

Procedure:
To a suitably equipped glass resin reactor equipped with stirrer are charged 100 parts bisphenol A, 70 parts toluene and 81.5 parts of aniline. The slurry is warmed and agitated to form a uniform solution. An inert nitrogen atmosphere is maintained over the reaction mixture. The temperature of the reaction mixture is adjusted to 50° C. and 108 parts of 50% formalin are added slowly, while the temperature is maintained at 50° to 55° C. After formalin addition is complete the batch is refluxed at 65° C. for 1 hour under reduced pressure. The batch is then heated to atmospheric reflux and the reflux condensate is permitted to separate into an aqueous phase and organic phase in an oil/water separator. The organic phase of the condensate is returned to the reactor and the aqueous phase is removed. After about 83 parts of water are removed and the reaction temperature reaches 116° C., the clear product solution is cooled while 21 parts of 2-butoxyethanol are added. The clear pale yellow solution of poly(dihydrobenzoxazine) had the following composition and properties: percent closed dihydrobenzoxazine ring 83%, equiv. wt. 278, solids 71.6%, Brookfield viscosity 305 cps.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][S:3]1.C1C=CC=CC=1.[Br:14][CH:15]([Br:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>O>[CH3:1][C:2]1([CH3:7])[N:6]([C:16](=[O:17])[CH:15]([Br:19])[Br:14])[CH2:5][CH2:4][S:3]1
Reactant: CC1(C)NCCS1
Reactant: O=C(Cl)C(Br)Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)SCCN1C(=O)C(Br)Br

Procedure:
To a mixture of 3.5 g. of 2,2-dimethyl thiazolidine, 50 ml. of benzene and 7.1 g. of dibromoacetyl chloride mixed in an ice bath was added 3.1 g. of triethylamine dropwise with stirring and continued cooling. When reaction was complete, the mixture was poured into water and the benzene layer separated, dried over magnesium sulfate and the benzene removed under vacuum. Yield was 8.5 g. of a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13]([C:14]3[NH:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[O:31])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: COc1ccnc2c(Sc3nc4ccccc4[nH]3)cccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccnc2c(S(=O)c3nc4ccccc4[nH]3)cccc12

Procedure:
The product of step (b) above (390 mg) in ethyl acetate (20 ml) was cooled to -5° and treated with m-chloroperbenzoic acid (273 mg of 85% pure material). The temperature was allowed to rinse to ambient. The reaction mixture was then diluted with ethyl acetate and methylene chloride, and then washed with sodium bisulphite solution, sodium bicarbonate solution and brine. The solution was dried and evaporated. Column chromatography (SiO2 /ethyl acetate) gave the title compound 140 mg, mp 178°-9° (d).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].P([O-])([O-])([O-])=O>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 1 h

Procedure:
To a glucose isomerase solution are added 0.1 M D-glucose, 0.05 M phosphate buffer solution and 0.005 M MgSO4.7H2O and, while maintaining pH at 7.0, the reaction is carried out at 70° C. for one hour. The amount of fructose formed is measured. One unit of activity is expressed as the amount of enzymes necessary for forming 1 mg of fructose under the above conditions.
Reaction SMILES: [CH2:1]=[O:2].S(=O)(=O)(O)O.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(C1C=CC=CC=1)C>C(O)CCC.O>[C:16]1([CH:1]=[O:2])[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: C=O
Reactant: c1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: CCc1ccccc1
Solvent: O
Product: O=Cc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 102.1 %

Procedure:
A bottom-removable four-necked flask having an inner volume of 2 L and equipped with a Dimroth condenser, a thermometer and a stirring blade was charged with 384 g of 86% by mass paraformaldehyde (11.0 mol as formaldehyde, produced by Mitsubishi Gas Chemical Company, Inc.), 437 g of ion-exchange water (produced by Mitsubishi Gas Chemical Company, Inc.), 297 g of 1-butanol (produced by Wako Pure Chemical Industries, Ltd.) and 398 g of 98% by mass sulfuric acid (produced by Mitsubishi Gas Chemical Company, Inc.) in a nitrogen stream, 256 g of naphthalene (2.0 mol, produced by Wako Pure Chemical Industries, Ltd.) was dropped thereto over 6 hours while stirring under reflux under ordinary pressure at about 100° C., and the reaction was performed as it was for further 2 hours. Thereto was added 500 g of ethylbenzene (produced by Wako Pure Chemical Industries, Ltd.) as a dilution solvent and left to still stand, and then an aqueous phase as a lower phase was removed. Furthermore, the resultant was subjected to neutralization and washing with water, and ethylbenzene and unreacted naphthalene were distilled off under reduced pressure to thereby provide 319 g of a naphthalene formaldehyde resin as a light yellow liquid.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCc1ccc(Br)cc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
95 g (0.39 mol) of 4-pentanoylbromobenzene, 300 ml of diethyleneglycol, 40 ml (0.80 mol) of 100% hydradine hydrate and 45 g (0.80 mol) of potassium hydroxide were heated at 130° C. for 1 hour and then at 180° C. with stirring for 3 hour. Water was added to the reaction solution and the organic layer was extracted with chloroform. After washing the extracted layer with water, the chloroform was removed by distillation. Then the residue was distilled under reduced pressure to yield 75.4 g of 4-pentylbromobenzene having at b.p. 87° to 90° C./2 mmHg.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:16]=[C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(OC(N1[CH2:37][CH2:36][CH:35]([C:38]2O[N:41]=[C:40](COC3C=CC(S(C)(=O)=O)=CC=3)[N:39]=2)[CH2:34]C1)=O)(C)(C)C.CCN(C(C)C)C(C)C.ClC1N=CC(CC)=CN=1>CC(O)C>[CH2:36]([C:35]1[CH:38]=[N:39][C:40]([N:20]2[CH2:21][CH2:22][CH:17]([C:15]3[O:14][N:13]=[C:12]([CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:24][CH:23]=4)[N:16]=3)[CH2:18][CH2:19]2)=[N:41][CH:34]=1)[CH3:37]
Reactant: CS(=O)(=O)c1ccc(OCc2noc(C3CCNCC3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)no2)CC1
Agent: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(c3nc(COc4ccc(S(C)(=O)=O)cc4)no3)CC2)nc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To the crude HCl salt (0.18 g, ˜0.5 mmol) of 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine, prepared by treatment of 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 81) in dixoane with 4N HCl, was added 2-propanol (3 mL), followed by DIPEA (0.13 g, 1 mmol) and 2-Chloro-5-ethyl-pyrimidine (0.14 g, 1 mmol). The resulting mixture was stirred at 70° C. overnight. After concentration in vacuo, the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product. 1H NMR (CDCl3): δ 8.18 (2H, s), 7.89 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.75˜4.65 (2H, m), 3.3˜3.2 (1H, m), 3.2˜3.1 (2H, m), 3.03 (3H, s), 2.47 (2H, q, J=7.6 Hz), 2.22˜2.16 (2H, m), 1.96˜1.84 (2H, m), 1.19 (3H, t, J=7.6 Hz).
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1>C(O)C>[C:1]([CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1)#[N:2]
Reactant: [C-]#N
Reactant: C=Cc1ccc(CCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=Cc1ccc(CC#N)cc1
Temperature: 65 °C

Procedure:
In a 500 μl 4-opening flask equipped with a stirring bar, 49.01 g of sodium cyanide was mixed with 70.07 g of water and 50.96 g of ethanol. Then, the temperature of the flask was elevated to 60° C. and the sodium cyanide was completely dissolved. To said solution, 87.50 g of 4-chloromethylstyrene was slowly added and it was reacted for 3 hours while stirring and maintaining the reaction temperature within 60-70° C. When the reaction terminated, said solution was cooled to 40° C., and 100 g of diethylether was added and the diethylether layer was separated. The separated organic layer was extracted with 300 g of water three times, and the water layer was extracted with 50 g of diethylether and was combined with said organic layer. The separated obtained organic layer was dried with magnesium sulfate for one day, and then the organic solvent was removed using an evaporator to obtain the product 4-cyanomethylstyrene. The yield of the product was 80%, and the product was a deep purple color.