Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH3:14]>O1CCCC1>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([C:10]([F:13])([F:12])[F:11])=[C:2]([NH2:14])[CH:7]=1
Reactant: Fc1cc(F)c(C(F)(F)F)cc1F
Reactant: N
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)cc1C(F)(F)F
Temperature: 140 °C

Procedure:
225 g of 2,4,5-trifluorobenzotrifluoride in 600 ml of tetrahydrofuran were initially introduced into an autoclave and it was pressurized using 100 ml of liquid ammonia. The mixture was heated at 140° C. for 8 hours with stirring at 400 rpm and then cooled to 20° C. After releasing the pressure of the unused ammonia, the batch was distilled. 37 g of 4,5-difluoro-2-aminobenzotrifluoride were obtained in the forerun. The main amount distilled at 78° C./18 mbar and is, according to NMR spectroscopic findings, 2,5-difluoro-4-amino-benzotrifluoride (nD20 : 1.4560) having a yield of 154 g.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[CH3:9][Si:10]([CH2:13][CH2:14][O:15][CH2:16]Cl)([CH3:12])[CH3:11].O>C1COCC1>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:16][O:15][CH2:14][CH2:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(I)cn1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A slurry of NaH (1.94 g, 48.5 mmol) in THF (40 mL) at 0° C. was treated with a solution of 4-iodopyrazole (8.97 g, 46.2 mmol) in THF (20 mL), stirred for 1 h, treated with SEM chloride (9.00 mL, 50.8 mmol), stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 14.4 g of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[C:10]([OH:23])=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2.CCN(C(C)C)C(C)C>CS(C)=O.O>[OH:23][C:10]1[C:9]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=2)[N:11]=1
Reactant: C[C@H]1COCCN1
Reactant: COC(=O)c1ccc2nc(O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(O)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of (3S)-3-methylmorpholine (200 mg, 1.98 mmol) in DMSO (10 mL) was added methyl 3-chloro-2-hydroxyquinoxaline-6-carboxylate (700 mg, 2.93 mmol), DIEA (510 mg, 3.95 mmol). The resulting solution was stirred overnight at 70° C. and then dissolved in water (100 mL), extracted with dichloromethane (4×30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 5%˜50% ethyl acetate in petroleum ether to afford methyl 2-hydroxy-3-[(3S)-3-methylmorpholin-4-yl]quinoxaline-6-carboxylate as a light yellow solid (210.0 mg).
Reaction SMILES: ClC1N=CN=C2C=1N=CN2[C@H]1[C@@H]2[O:16]C(C)(C)O[C@@H]2[C@@H](CO)C1.C(NS(=O)=O)(OC(C)(C)C)=O.[C:34]1([P:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CCOC(C)=O>[C:47]1([P:40](=[O:16])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Agent: CC(C)(C)OC(=O)N[SH](=O)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((3aR,4R,6R,6aS)-[6-(6-chloro-purin-9-yl)-2,2-dimethyltetrahydro-cyclopenta[1,3]dioxol-4-yl]-methanol (Yang, M.; Wei, Y.; Schneller, S. W. J. Org. Chem. 2004, 69, 3993-3996) (250.0 mg, 0.77 mmol), N-Boc-sulfonamide (226.6 mg, 1.16 mmol) and triphenylphosphine (242.3 mg, 0.92 mol) in EtOAc (8 mL) was added diisopropyl azodicarboxylate (227.3 μL, 1.16 mmol) dropwise as a solution in EtOAc (1 mL). The reaction was stirred at r.t. overnight, quenched with water and extracted with EtOAc. The organics were concentrated and the residue purified by flash chromatography (0 to 100% EtOAc/DCM) to obtain the product as an inseparable mixture with triphenylphosphine oxide. The material was carried on as such.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](O)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:12]1([C:18](=[S:21])[NH:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[S:21][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:19][N:20]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: NNC(=S)c1ccccc1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)s1
Reaction time: 2 h
Yield: 43 %

Procedure:
3-amino-6-bromo-pyrazine-2-carboxylic acid (1.000 g, 4.588 mmol) and benzenecarbothiohydrazide (759.1 mg, 4.588 mmol) were suspended in acetonitrile (25.00 mL), cooled in an ice bath and then treated with dibromo-triphenyl-phosphorane (4.453 g, 10.55 mmol) The reaction mixture was allowed to stir in an ice bath for 2 hours and then DIPEA (1.778 g, 2.396 mL, 13.76 mmol) was added slowly at 10° C. The reaction was left to stir at 0-10° C. for a further hour and the resultant precipitate was isolated by filtration, washed with a small amount of acetonitrile and dried (659 mg, 43% Yield). MS (ES+) 335.93
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:37]=[CH:36][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#[N:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:38][CH3:39])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:40](P(=O)(OCC)OCC)[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44].CN(C)C=O.[H-].[Na+]>O>[C:31]([C:30]1[CH:29]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][O:20][C:19]3[CH:36]=[CH:37][C:16]([CH2:15][O:14][C:4]4[C:3](/[CH:1]=[CH:40]/[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])=[CH:7][N:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:5]=4)=[CH:17][C:18]=3[O:38][CH3:39])[N:23]=2)[CH:35]=[CH:34][CH:33]=1)#[N:32]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C#N)c3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (2.50 g), tetraethyl methylenediphosphonate (1.53 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.23 g) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl [(E)-2-{3-[(4-{[2-(3-cyanophenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl]phosphonate as colorless crystals (2.20 g, yield 70%) from a fraction eluted with ethyl acetate-hexane (4:1 to 9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 147-148° C.
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:16])([C:13](=[O:15])[CH3:14])[CH3:12])=[CH:7][CH:6]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>O>[O:17]([C:24]1[CH:25]=[C:26]([CH:27]=[CH:14][C:13](=[O:15])[C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=2)([CH3:16])[CH3:12])[CH:29]=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)C(C)(C)c1ccc(C)cc1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(C)(C)C(=O)C=Cc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To 50 ml of ethanol were added 5.3 g of 2-(4-methylphenyl)-2-methyl-3-butanone, 6.0 g of 3-phenoxybenzaldehyde and 6.0 g of KOH, and the mixture was stirred at room temperature for one hour and 20 minutes. Then, the reaction mixture was poured into 300 ml of water and extracted with benzene. The benzene extract was washed with water and dried, and the solvent was evaporated under reduced pressure to give 10.4 g of crude 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-penten-3-one. Then, the crude produce was purified by column chromatography on 250 g of silica gel (eluent: benzene) to give 6.8 g of pure 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-penten-3-one.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:12]=2[CH3:28])[CH2:5][O:4]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:37])[C:12]=2[CH3:28])[CH2:5][O:4]1
Reactant: COC1OCC(COc2ccnc(CSc3nc4ccccc4[nH]3)c2C)CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a toluene/methanol (10:1) (20 ml) solution of the 2-(((4-((2-methoxy-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (324 mg, 807 μmol) obtained in the step (6d), a toluene/methanol (10:1) (5 ml) solution of 3-chloroperbenzoic acid (193 mg, 726 μmol as the content was regarded as 65%) was added dropwise at −50° C. to −60° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 2 hours in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (222 mg, 65.9% yield), which is a cis and trans (1:1) mixture, as a light yellow foam.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[C:10]3[C:9]2=[O:25])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:32]1(B(O)O)[CH2:34][CH2:33]1>CN(C=O)C.O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:32]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]4[N:14]=[C:15]([CH2:17][O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:16]=[C:10]4[C:9]3=[O:25])[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33]1
Reactant: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(Br)n1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(C2CC2)n1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol), was added to a stirred suspension of 5-(6-bromo-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.12 mmol), potassium carbonate (52 mg, 0.37 mmol), cyclopropylboronic acid (21.5 mg, 0.25 mmol) in a mixture of DMF (0.5 mL) and 1,4-dioxane (0.5 mL) in a sealed tube and under nitrogen. The mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The mixture was diluted with water and extracted with AcOEt. The organic layer was washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with heptane to yield 5-(6-cyclopropyl-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (28 mg, 62% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 0.93-1.03 (m, 4H), 1.97-2.06 (m, 1H), 4.44-4.58 (m, 4H), 5.12 (s, 2H), 6.93-7.04 (m, 4H), 7.05 (s, 1H), 7.27-7.34 (m, 2H), 7.58 (t, J=7.8 Hz, 1H), 7.74-7.80 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=O)[C:12]([O-:14])=[O:13])=[CH:2]1.[NH2:16][C@H](C(O)=O)CC(O)=O.[Mg+2].[Cl-].[Cl-].[C:28]([CH2:33]C([O-])=O)([C:30]([OH:32])=[O:31])=[O:29]>>[NH2:16][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1.[C:30]([OH:32])(=[O:31])[C:28]([CH3:33])=[O:29]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C([O-])CC(=O)C(=O)O
Reactant: O=C([O-])C(=O)Cc1c[nH]c2ccccc12
Agent: [Cl-]
Agent: [Mg+2]
Product: CC(=O)C(=O)O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 2 h

Procedure:
A solution of indole-3-pyruvate, 20 mM; L-aspartic acid 20 mM; MgCl2, 1.5 mM; transaminase, 0.3 mg/ml; oxaloacetate decarboxylase, 0.3 mg/ml buffered to pH 7.0 with 5 mM tris-hydroxymethylaminomethane hydrochloride (Tris) was stirred slowly for 2 hours. At the end of this time the reaction is complete. The L-tryptophan and pyruvic acid produced can be purified by methods well known in the art.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[IH:19]>>[I:19][C:12]1[CH:17]=[C:16]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:15]=[CH:14][N:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: Fc1ccc(-c2cc(I)ncn2)cc1

Procedure:
The compound was prepared according to Example 1 using 4-fluorophenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C(OCC)C>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOCC
Solvent: CCCCN(CCCC)CCCC
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 97 %

Procedure:
To a suspended ethyl ether (2 ml) solution of 2-chloro-1-methylpyridinium iodide (306 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and tri-n-butylamine (444 mg, 2.4 mmol) in ethyl ether (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 97% yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:17]([OH:19])=O)=[N:12][CH:13]=[CH:14][C:15]=1[Cl:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([C:24]1[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:31][C:26]1[CH:25]=[C:24]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:29]=[CH:28][C:27]=1[NH:30][C:17](=[O:19])[C:11]1[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[C:15]([Cl:16])[CH:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Cl)ccnc1C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)c2nccc(Cl)c2CO[Si](C)(C)C(C)(C)C)c(N)c1
Temperature: 19 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
A mixture of 160e (20 g, 66 mmol), 4-(tert-butyl)benzene-1,2-diamine 160f (10.8 g, 66 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30 g, 79 mmol) and diisopropylethylamine (17 g, 132 mmol) in N,N-dimethylformamide (1000 mL) was stirred at 19° C. for 12 h. See FIG. 5. TLC (petroleum ether:ethyl acetate=1:1) showed that the starting material was completely consumed. The mixture was diluted with water (1000 mL) and extracted with EtOAc (1000 mL×2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=1:1) to afford N-(2-amino-4-(tert-butyl)phenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloropicolinamide 160g (20 g, 67%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9]C)=[O:7])=[CH:4][CH:3]=1.[O:13]1[CH2:18][CH2:17][CH:16](O)[CH2:15][CH2:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[O:13]1[CH2:18][CH2:17][CH:16]([O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OC1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OC2CCOCC2)cc1
Temperature: 21 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (500 mg, 3.0 mmol), tetrahydro-2H-pyran-4-ol (307.3 mg, 3.0 mmol) and PPh3 (944 mg, 3.6 mmol) in THF (15 mL) was added DEAD (627 mg, 3.6 mmol) at 0° C. The mixture was the warmed to 21° C. and stirred for 16 h. The mixture was treated with water and the organic layer was washed with brine, dried over Na2SO4, concentrated and the residue was purified by column chromatography to give the title compound (320 mg, Yield 45%). 1H NMR (CDCl3, 400 MHz): δ 7.92 (d, J=8.9 Hz, 1H), 6.75-6.94 (m, 1H), 4.44-4.59 (m, 1H), 4.28 (d, J=7.2 Hz, 2H), 3.83-4.00 (m, 2H), 3.46-3.60 (m, 2H), 1.88-2.05 (m, 2H), 1.67-1.83 (m, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][C:12](=[O:33])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][C:12](=[O:33])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)NCc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(CNC(=O)CNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10.5 g (0.0225 M) of benzyl{[[2-(o-fluorobenzoyl)-4-nitrophenyl]methylcarbamoyl]methyl}carbamate dissolved in 150 ml of glacial acetic acid are treated with 23 g of stannous chloride and 30 ml of a mixture of concentrated hydrochloric acid and water (1:1). The mixture is stirred at room temperature for 20 hours, poured on to ice/ammonia and extracted several times with ethyl acetate. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is purified on a 350 g silica gel column using methylene chloride/ethyl acetate as the eluting agent and crystallised from methylene chloride/ether. There is obtained benzyl{[[4-amino-2-(o-fluorobenzoyl)phenyl]methylcarbamoyl]methyl}carbamate which melts at 83° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[I:14]Cl>C(O)(=O)C>[NH2:1][C:2]1[C:11]([I:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: ClI
Reactant: COC(=O)c1ccc(N)cc1OC
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(N)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of methyl 4-amino-2-methoxybenzoate (13 g, 0.07 mol) in acetic acid (300 mL) was added dropwise a solution of iodine monochloride (11.5 g, 0.07 mol) in acetic acid (50 mL). The mixture was stirred for 1.5 hours at room temperature. The precipitate was filtered and washed with ether. Then was dissolved with bicarbonate 4% and extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was removed under reduced pressure giving the title compound as a white solid (88%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].[H][H]>>[CH3:8][C@H:7]1[CH2:9][C:10](=[O:11])[C@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:5][CH2:6]1
Reactant: CC(C)=CCCC(C)CCO
Reactant: [H][H]
Product: CC(C)[C@@H]1CC[C@@H](C)CC1=O

Procedure:
A process for producing menthol which comprises dehydrogenating citronellol in a reaction system containing a Raney-type catalyst or a metal oxide catalyst at a temperature of about 150° to about 260° C in an atmosphere of hydrogen under a pressure of 0 to about 5 kg/cm2.G to produce menthone as claimed in claim 1, and then, in the same reaction system without separating the catalyst or adding additional catalyst, hydrogenating the menthone produced by decreasing the temperature to about 110° to about 130° C and increasing the hydrogen pressure to about 10 to about 50 kg/cm2 to produce menthol.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=[C:7]3[C:8](=[O:16])[CH:9]2[CH2:13][CH2:14][Cl:15])[CH:4]=[N:3]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:39][CH2:40][NH2:41])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>CCOCC>[ClH:15].[ClH:15].[CH3:1][C:2]1([CH3:28])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=[C:7]3[C:8](=[O:16])[CH:9]2[CH2:13][CH2:14][NH:41][CH2:40][CH2:39][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[CH:32]=2)[CH:4]=[N:3]1
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC1(C)N=CC2=C3N=C(CCc4ccccc4)N=C3C(=O)C(CCCl)C2C1=O
Solvent: CCOCC
Product: COc1ccc(CCNCCC2C(=O)C3=NC(CCc4ccccc4)=NC3=C3C=NC(C)(C)C(=O)C32)cc1OC
Product: Cl

Procedure:
2.8 gm of 7,7-dimethyl-2-phenethyl-5-(2-chloro-ethyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were heated at 150° C. for 40 minutes with 5 ml of 2-(3,4-dimethoxy-phenyl)-ethylamine. After cooling, the mixture was dissolved in ether, and the solution was several times extracted with water weakly acidified with acetic acid. The organic phase was evaporated, and the residue was dissolved in acetone. The dihycrochloride was precipitated from the acetone solution with ethereal hydrochloric acid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[C-:23]#[N:24].[Na+]>CN(C=O)C>[CH:17]1([NH:16][C:4]2[N:3]=[C:2]([C:23]#[N:24])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nc(NC2CCCCC2)c2ncn(C3CCCC3)c2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(NC2CCCCC2)c2ncn(C3CCCC3)c2n1
Temperature: 25 °C

Procedure:
2-Chloro-6-cyclohexylamino-9-cyclopentyl-purine (6.3 mmol) and sodium cyanide (36 mmol) are heated up in DMF (30 ml) to 160° C. for 70 hours. After cooling down to RT the mixture is poured on water and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine and the extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with ethyl acetate as mobile phase. The product containing fractions are combined and evaporated. A pale yellow oil with Rf=0.33 (ethyl acetate) is obtained.