Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][C@H:5]([CH3:9])[C:6](O)=[O:7].C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][C@H:5]([CH3:9])[C:6]([Cl:24])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)Cl
Temperature: 75 °C

Procedure:
A stirred mixture of (R)-2-(2,4-dichlorophenoxy)propionic acid (588 g, 2.5 mol), 588 g of toluene and 0.6 g of dimethyl formamide (DMF) is heated to 75° C., treated with thionyl chloride (304 g, 2.55 mol) over a 1.5 hour period, heated at 75° C. for 1 hour and cooled to 20-25° C. The resultant reaction mixture may be distilled to obtain the title product in quantitative yield, as an amber oil, or used as is in the next process step. The isolated product is characterized by NMR analysis. The product toluene solution is assayed by HPLC analysis.
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[C:10]([NH2:11])=[CH:9][C:8]([CH3:12])=[N:7]2)[CH3:5])[CH2:3][CH2:2]1.[CH:13]1([C:16](=O)[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH:13]1([C:16]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]3[C:8]([CH3:12])=[N:7][N:6]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:5])[C:10]=3[N:11]=2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C(C)C2CC2)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)C1CC1
Temperature: 70 °C

Procedure:
1-(1-Cyclopropylethyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 3.03 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (557 mg, 3.03 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 16 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% EtOAc:Hex). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=314.3 1H NMR (400 MHz, DMSO-d6) ppm 0.17-0.32 (m, 2H), 0.39 (m, J=9.69, 4.82, 4.82, 4.67 Hz, 1H), 0.51-0.62 (m, 1H), 0.94-1.11 (m, 4H), 1.28-1.41 (m, 4H), 1.58 (d, J=6.82 Hz, 3H), 2.30-2.38 (m, 1H), 2.56 (s, 3H), 4.19 (dq, J=9.44, 6.87 Hz, 1H), 4.43 (q, J=7.07 Hz, 2H), 7.48 (s, 1H)
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:3])[CH3:2].S([O-])([O-])(=O)=O.[Ba+2]>O1CCCC1.C(O)C.[Pd]=O>[C:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C=Cc2oc3ccc(C#N)cc3c2C(C)=O)cc1
Agent: O=[Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(C)=O)cc1
Reaction time: 3.5 h
Yield: 69.7 %

Procedure:
1H-NMR (CDCl3) δ: 2.69 (3H, s), 3.85 (3H, s), 6.98 (2H, d, J=10 Hz), 7.50-7.80 (6H, m), 8.36 (1H) d) 7.8 g of 3-acetyl-2-[2-(4-methoxyphenyl)-vinyl]-5-benzofurancarbonitrile obtained in the above step c) was dissolved in a solvent mixture of 600 ml of tetrahydrofuran and 500 ml of ethanol. 900 mg of palladium oxide.1H2O.barium sulfate was added to the above solution, and the mixture was subjected to catalytic hydrogenation under normal pressure for 3.5 hours. After removing the catalyst by filtration, the resulting filtrate was concentrated to dryness. The residue thus obtained was extracted with ethyl acetate, and the resulting organic layer was washed with water, and dried to distill off the solvent. Thereafter, the residue thus obtained was washed with methanol to collect precipitated crystals by filtration, thereby obtaining 5.47 g of 3-acetyl-2-[2-(4-methoxyphenyl)ethyl]-5-benzofurancarbonitrile in the form of colorless prism crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1>C(O)C>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
4-Aminophenol (1.09 g, 10 mmol) and 4,7-dichloroquinoline (1.98 g, 1 eq) were refluxed in 50 mL of ethanol for 2 h. The reaction mixture was then cooled to room temperature and the precipitate was removed by filtration and washed successively with a saturated aqueous solution of NaHCO3, water, methanol and then petroleum ether to yield expected compound as a yellow powder (2.57 g, 95% yield). m/z (ESI) 271.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CS([O-])(=O)=O.[CH2:17]([N:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22]O)[CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH3:25])[CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCN(CC)CCCO
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1

Procedure:
A solution of 3-fluoro-4-nitrophenol (2 mmol) and methanesulfonate of 3-diethylamino-1-propanol (2.5 mmol) in DMF (4 mL) is added with K2CO3 (4 mmol) and heated following the general procedure III (Step A). The product, 2-fluoro-4-(3-diethylamino-1-propoxy)nitrobenzene is obtained (470 mg) after purification using silica gel column chromatography.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14](Cl)=[O:15])([CH3:10])([CH3:9])[CH3:8]>[OH-].[Na+].C1COCC1>[C:21]([C:18]1[CH:17]=[C:13]([C:14]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[O:15])[CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:19]=1[OH:20])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: OC1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)N2CC(O)C2)cc(C(C)(C)C)c1O
Temperature: -5 °C
Yield: 28.6 %

Procedure:
Azetidin-3-ol hydrochloride (2 g, 18,3 mmoles) was dissolved in a 5% weight/weight (45 ml) of an aqueous solution of sodium hydroxide, the resulting solution cooled to −5° C. and under vigorous stirring 3,5-di-tert-butyl-4-hydroxy-benzoyl chloride (5,4 g, 20 mmoles) obtained according to step (a) dissolved in 8 ml of THF was added. Afterwards the cooling bath was removed, the reaction mixture warmed to room temperature (approximately 25° C.) and stirred for an additional hour under these conditions. The reaction mixture was then extracted several times with diethyl ether, the etherical phases combined, washed with water, dried with sodium sulfate and evaporated to dryness to obtain 1,9 g of the crude product, which is crystallized from ethyl acetate-petroleum ether. 1,6 g (30% of theoretical yield) of (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone were obtained in crystalline form.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([SH:11])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([S:11][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)CCBr
Reactant: CC(C)(C)S
Product: CC(C)CCSC(C)(C)C
Yield: 86 %

Procedure:
The title compound was prepared from isoamyl bromide and tert-butyl mercaptan according to the method of Example 1, 86% yield, bp 55°-56° C./7 mm Hg, n20D=1.4460; 1H NMR (CDCl3) δ 0.92 (d, J=6 Hz, 6H, CH3), 1.32 (s, 9H, CH3), 1.45 (q, 2H, CH2), 1.68 (septet, 1H, CH), 2.52 (t, J =6 Hz, 2H, CH2).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[NH:18][CH2:17][CH2:16]2)[CH3:5])[CH:2]=[CH2:3].[CH2:30]=O.[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[N:18]([CH3:30])[CH2:17][CH2:16]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCOc1ccc2c(c1)CCNC2c1ccc(Br)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)CCN(C)C2c1ccc(Br)cc1
Temperature: 65 °C

Procedure:
0.1 g of (RS)-allyl-[6-[1-(4-bromo-phenyl)-1,2,3,4-tetra-hydro-isoquinolin-6-yloxy]-hexyl]-methyl-amine (Ex. 21) is taken up in 2 ml of a 1M NaH2PO3 solution and treated with 2 ml of dioxan as a solubilizer. After the addition of 2 ml of a 37% aqueous formaldehyde solution the mixture is heated to 65° C. for 48 hrs. For the working-up, the mixture is adjusted to pH >12 with 4M aqueous sodium hydroxide solution and extracted with ethyl acetate. After evaporation of the extracts and chromatography of the residue (silica gel, toluene/acetone/triethylamine, 25:74:1) there is obtained 0.12 g of (RS)-allyl-[6-[1-(4-bromo-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-hexyl]-methyl-amine which is converted into its hydrochloride, MS: m/e 471 (M+H+, 1 Br).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[C:3]([F:15])=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:28]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(N)c1F
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])cc(NC(=O)CCCCl)c1F
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of methyl 3-amino-2-fluoro-5-nitrobenzoate (D138) (12 g, 56 mmol, 1 equiv) in CH2Cl2 (150 ml) at room temperature were added NEt3 (11.7 ml, 84 mmol, 1.5 equiv) and 4-chlorobutanoyl chloride (6.9 ml, 61.6 mmol, 1.1 equiv) and the resulting mixture was stirred for 2 h then washed with a 2N aqueous HCl solution and a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 4/1) gave methyl 3-[(4-chlorobutanoyl)amino]-2-fluoro-5-nitrobenzoate (D139) (16.2 g, 91%) as a yellow solid. [M+H]+=319.1, RT=3.12 min.
Reaction SMILES: C(=O)([O-])O.[Na+].O1CCCC1.[NH2:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14].[CH3:20][C@@H:21]([C@@H:28]1[C@@:32]2([CH3:50])[CH2:33][CH2:34][CH:35]3[C@@:40]4([CH3:49])[CH2:41][CH2:42][CH:43]([O:45][C:46](Cl)=[O:47])[CH2:44][C:39]4=[CH:38][CH2:37][CH:36]3[CH:31]2[CH2:30][CH2:29]1)[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>O>[CH3:27][CH:25]([CH2:24][CH2:23][CH2:22][C@H:21]([C@@H:28]1[C@:32]2([CH3:50])[C@H:31]([C@H:36]3[C@H:35]([CH2:34][CH2:33]2)[C@:40]2([CH3:49])[C:39]([CH2:44][C@@H:43]([O:45][C:46]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[O:47])[CH2:42][CH2:41]2)=[CH:38][CH2:37]3)[CH2:30][CH2:29]1)[CH3:20])[CH3:26]
Reactant: NCC(=O)NCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 80.8 %

Procedure:
Sodium hydrogencarbonate (0.168 g) and tetrahydrofuran (20 ml) were added to a suspension of glycylglycine (0.15 g) in water (20 ml). After tetrahydrofuran (20 ml) and cholesteryl chloroformate (0.898 g) were added to the resulting transparent solution at 0° C., the mixture was stirred for an hour. The reaction mixture was concentrated under reduced pressure and, methanl (10 ml) and chloroform (10 ml) were added to the residue. By filtration, the transparent solution was obtained. The solvent was distilled off to give crude crystals (0.98 g). The crude crystals were then purified by silica gel chromatography to give N-(cholest-5-ene-3β-oxycarbonyl)glycylglycine (0.5 g) as white powders.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH3:9]>C(O)C>[CH2:1]([O:3][C:4]([NH:6][C:7]([NH2:9])=[S:8])=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)N=C=S
Solvent: CCO
Product: CCOC(=O)NC(N)=S
Reaction time: 2 h

Procedure:
To 0.1 mole of ethoxycarbonyl isothiocyanate in ethanol (50 ml) is added 50 ml of a 2M ethanolic solution of ammonia. After 2 hours at room temperature, the precipitated product is collected by filtration and used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(Cl)c(C#N)cc1[N+](=O)[O-]
Product: Cc1cc(Cl)c(C(N)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 25.1 grams 2-chloro-4-methyl-5-nitrobenzonitrile (Weissberger et al, J. Chem, Soc., p.68 (1935) and 200 ml 70% sulfuric acid was heated with stirring on a steam bath for 41/2 hours. A precipitate started to form after this time and the mixture was poured into ice water (about 400 ml). The product was filtered, washed with water and recrystallized from ethanol. Yield = 19.2 grams. m.p. = 180°-183° C.
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=C)=[O:12])([CH3:9])([CH3:8])[CH3:7].O=O.S(C)C>C(Cl)CCl>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=[O:4])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C=C[C@H](OC(C)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCCl
Product: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Ozone/oxygen was bubbled at -70° C. into a solution of (3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene (2.55 g, 8.0 mmol) [prepared by the method of Hanson et al, J. Org. Chem., 50, 5399 (1985)] in 100 mL of ethylene chloride until a deep blue color persisted. Oxygen was introduced until the blue color completely faded, then 3.0 mL of Me2S was added and the solution was allowed to arm to 0°-5° C. and stand overnight. The solvent was removed at 0° C. under vacuum yielding the title compound as a thick yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:4]([CH2:16][CH3:17])[N:3]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=2)=[C:4]([CH2:16][CH3:17])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
In this method, commercially available 2,4-diamino-6-ethyl-5-(4-chlorophenyl)pyrimidine is nitrated with 70% nitric acid and concentrated sulfuric acid, yielding the corresponding 2,4-diamino-6-ethyl-5-(4-chloro-3-nitrophenyl)pyrimidine. The thus-prepared nitrophenylpyrimidine is in turn reduced with stannous chloride dihydrate in 10M hydrochloric acid, yielding the corresponding 2,4-diamino-6-ethyl-5-(3-amino-4-chlorophenyl)pyrimidine. The aminophenylpyrimidine may then be treated with an appropriate acid chloride in the presence of a base in tetrahydrofuran, yielding the desired 2,4-diamino-6-ethyl-5-[3-(substituted-carbonylamino)-4-chlorophenyl]pyrimidine (wherein W is --NHC(O)R4). These compounds may optionally be reduced with 1M boron-tetrahydrofuran complex in tetrahydrofuran, affording 2,4-diamino-6-ethyl-5-[3-(substituted-amino )-4-chlorophenyl]pyrimidine (wherein W is --NHR5).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])O.[Na+].Cl[CH2:15][C:16](=[O:18])[CH3:17].[OH-].[Na+]>O.C(O)(C)C>[CH2:15]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[C:16]([CH3:17])=[O:18]
Reactant: CC(=O)CCl
Reactant: Oc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)COc1ccccc1O
Reaction time: 4 h
Yield: 46.6 %

Procedure:
11 g of catechol, 16.8 g of sodium hydrogencarbonate and 9.5 g of monochloroacetone were dissolved in a mixed solvent of 300 ml of water and 100 ml of isopropyl alcohol, and the solution was heated up to 50° to 60° C. and then stirred for 4 hours. Afterward, 50 ml of a 8% aqueous sodium hydroxide solution and 9.3 g of monochloroacetone were further added, followed by stirring at 50° C. for 5 hours. After standing for cooling, insolubles were removed from the solution by filtration, and the resultant filtrate was concentrated until the volume of the solution became about 300 ml, and then extracted with chloroform. The chloroform layer was washed with a dilute aqueous sodium hydroxide solution and then with water. The solvent was distilled off, and the residue was purified through a silica gel column chromatograph (chloroform/hexane=7/3 to chloroform alone in volume ratio), and then recrystallized from ether/hexane, thereby obtaining 7.73 g of crystals of 2-acetonyloxyphenol.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:20])[CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:13][N:14]([CH3:20])[CH:15]1[CH2:19][CH2:18][N:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CN(C)C1CCNC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(N(C)C)C2)cc1
Temperature: 130 °C

Procedure:
A mixture of ethyl 4-fluorobenzoate (4.47 g), dimethylpyrrolidin-3-ylamine (3.04 g), potassium carbonate (3.68 g) and dimethyl sulfoxide (20 ml) was heated at 130° C. for 7 hours. After cooling, the mixture was diluted with water and extracted with methyl tert-butyl ether. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 262.35 (C15H22N2O2) was obtained in this way; MS (ESI): 263 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:29])[F:27])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:30](=[O:32])[CH3:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine were added. The reaction was shaken at room temperature overnight. The solvent was removed in vacuo, the residue was dissolved in DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentration in vacuo afforded 27 mg of the title compound as hydrochloride salt. Yield 40% ES MS m/z 439
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](OC1C=CC(C(C2C=CC=CC=2)=O)=CC=1)[CH:17]=[CH2:18]>>[CH2:18]([C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH:17]=[CH2:16]
Reactant: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Product: C=CCc1cc(C(=O)c2ccccc2)ccc1O
Yield: 46.2 %

Procedure:
4-hydroxybenzophenone (25 g) was converted to 4-allyloxybenzophenone (29.2 g, yellow solid) by the procedure of Example 23. Claisen rearrangement using that procedure gave 13.5 g (47%) of desired 3allyl-4-hydroxybenzophenone, the balance being recovered. Finally, acylation of 3-allyl-4-hydroxybenzophenone (5.9 G) according to general procedure of Example 1 produced 6.9 g (86%) of product as yellow solid.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[N:14]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)=[N+:15]=[N-:16].N1C=CC=CC=1C1C=CC=CN=1>CN(C=O)C.CCOC(C)=O>[OH:23][C:19]1[CH:18]=[C:17]([N:14]2[CH:3]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=3)[N:16]=[N:15]2)[CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=Nc1cccc(O)c1
Reactant: C[Si](C)(C)C#Cc1cccc(O)c1
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Oc1cccc(-c2cn(-c3cccc(O)c3)nn2)c1
Temperature: 80 °C
Yield: 69.5 %

Procedure:
To 3-TMSE-phenol (4.0 g, 21.02 mmol) in 35 mL of DMF were added 3-azidophenol (3.41 g, 25.2 mmol), CuBr (153 mg, 1.05 mmol), and 2,2′-bipyridyl (328 mg, 2.10 mmol). The mixture was heated at 80° C. for 24 h, cooled to room temperature, then diluted with 250 mL of EtOAc. The combined organic mixture washed with water, and dried over MgSO4. Solvents were removed by rotary evaporation, and the residue was recrystallized in acetic acid/water to give 3.70 g (70% yield) of a brown crystalline solid. 1H NMR (MeOD-d4, 300 MHz, ppm): 8.80 (s, 1H, triazol-H), 7.43-7.26 (m, 6H, Ar—H), 6.95-6.91 (m, 1H, Ar—H), 6.84-6.83 (m, 1H, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 158.6, 157.7, 148.1, 137.9, 131.1, 130.4, 129.7, 118.8, 116.7, 115.6, 115.1, 112.1, 110.7, 107.1.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[SH:8][CH2:9][CH2:10][CH2:11][OH:12].[NH2:13][C:14]1[N:22]=[C:21](Cl)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cl-].[Na+].O>[NH2:13][C:14]1[N:22]=[C:21]([S:8][CH2:9][CH2:10][CH2:11][OH:12])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: OCCCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SCCCO)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
Sodium hydride (600 mg, 15 mmol 60% in mineral oil) were added DMF (10 ml), 3-mercapto-1-propanol (1 ml, 12 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred at 100° C. for 2 hours. After addition of saturated brine the reaction mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (30 mg, yield 12%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[OH:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:13]([NH:12][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)=[CH:19][CH:20]=1)=[S:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: N[C@H](CCO)c1ccccc1
Product: OCC[C@@H](NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccccc1

Procedure:
The title compound was prepared with (R)-3-amino-3-phenylpropan-1-ol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.270 g, 64%): mp 162-165° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.37 (d, J=1.8 Hz, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.07-8.01 (m, 4H), 7.63-7.61 (m, 4H), 7.35-7.34 (m, 4H), 7.25-7.26 (m, 1H), 5.58 (s, 1H), 4.65 (s, 1H), 3.39-3.40 (m, 2H), 1.90-2.03 (m, 2H); ESIMS m/z 514 ([M+H]+).