Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([NH:42][CH:43]3[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44]3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:55]=[CH:56][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([NH:42][CH:43]3[CH2:47][CH2:46][NH:45][CH2:44]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C(=O)OC(C)(C)C)C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(NC3CCNC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
A round-bottomed flask was charged with tert-butyl 3-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)pyrrolidine-1-carboxylate (61.3 mg, 0.08015 mmol), 2,2,2-trifluoroacetic acid (182.8 mg, 1.603 mmol) and CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (40.8 mg, 76.58%). LRMS (APCI pos) m/e 665 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[O:32][N:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[CH:34]=[C:33]([CH3:35])[O:32][N:31]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: Cc1cc(CBr)no1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(CN2C[C@@H](C)n3c(cc4cc(OC5CCN(C(C)C)CC5)ccc43)C2=O)no1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 3-(bromomethyl)-5-methylisoxazole, to give the desired product as a yellow oil (76%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.F>O>[C:9]([O:7][C:1]1[CH:6]=[CH:5][C:4]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:13](=[O:15])[CH3:12])=[CH:17][CH:16]=2)=[O:15])=[CH:3][CH:2]=1)(=[O:8])[CH3:10]
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: F
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)c2ccc(OC(C)=O)cc2)cc1
Yield: 151.5 %

Procedure:
45.5 g (0.52 mole) of phenol, 69.0 g (0.50 mole) of 4-hydroxybenzoic acid, and 500 mL of hydrogen fluoride were heated together for 6 hr under autogenous pressure in an autoclave. Then the contents were mixed in excess water to precipitate a pink solid. Yield was 99 g (92.5%). The crude product was acetylated directly, without purification, by refluxing 2 hr in 3 times its volume of acetic anhydride and about 8 drops of sulfuric acid. Precipitation in excess water yielded 113 g of 4,4'-diacetoxybenzophenone of such high purity that no recrystallization was required (melting point 150-152° C. ).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A 15-mL, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid (0.075 g, 0.274 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (0.063 g, 0.411 mmol) 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (0.079 g, 0.411 mmol), 1-hydroxybenzotriazole (0.037 g, 0.274 mmol), diisopropylethylamine (0.141 g, 1.09 mmol), and DMF (1.0 mL). After stirring at ambient temperature for 18 h, the reaction was concentrated under reduced pressure and purified by preparative HPLC to afford 0.016 g (14% yield) of N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.95 (br s, 1H), 8.23 (d, J=6.9 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.65-7.57 (m, 3H), 4.58 (q, J=7.1 Hz, 1H), 3.18 (br s, 2H), 2.58 (m, 5H), 2.25-2.02 (m, 3H), 1.55 (s, 3H), 1.23 (m, 3H); MS (APCI) m/z 409 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:14]=2[O:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[C:14]=2[O:13]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2cccc(Oc3ncccc3[N+](=O)[O-])c2O1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A solution of 2-chloro-3-nitropyridine (4.9 g, 30.9 mmol) in DMF (50 mL) was treated with 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol (5.3 mL, 46.4 mmol) and cesium carbonate (30.2 g, 92.7 mmol). The mixture was heated at 80° C. for 10 h. The reaction was cooled to rt, and the mixture was poured in water (200 mL) with stirring. The yellow precipitate formed was filtered and washed with water, and recrystallized from ethanol (50 mL) to afford 134a as brown crystals (6.5 g, 73% yield). [M+H]+=287.16. 1H NMR (500 MHz, deuterochloroform) δ ppm 8.38 (dd, 1H, J=1.7 Hz, J=5.0 Hz), 8.31 (dd, 1H, J=5.0 Hz, J=1.7 Hz), 7.12 (dd, 1H, J=10.0 Hz, J=5.0 Hz), 7.05 (d, 1H, J=5.0 Hz), 7.00 (d, 1H, J=10.0 Hz), 6.86 (t, 1H, J=10.0 Hz), 3.05 (s, 2H), 1.39 (s, 6H); 13C (125 MHz, deuterochloroform) δ (ppm), 155.42, 151.76, 150.16, 136.03, 135.40, 134.04, 129.76, 122.60, 121.06, 120.37, 118.07, 88.40, 43.07, 27.98.
Reaction SMILES: C1([Li])C=CC=CC=1.[CH3:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[N:11][C:10]=1[CH3:17].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=1>CCOCC>[OH:25][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:26])=[CH:19][CH:20]=1)[CH2:17][C:10]1[C:9]([CH3:8])=[N:14][C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: Cc1ccc(C(O)Cc2nc(C)c(C)nc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a solution of phenyllithium in 150 milliliters 7:3 benzene-ether (0.1 mole) at 0° C. was slowly added a solution of 13.6 grams of tetramethylpyrazine (0.1 mole). The mixture was stirred at room temperature for 2 hours and heated under reflux for 1.5 hours. The mixture was cooled to 0° C., and a solution of 12.0 grams of p-tolualdehyde (0.1 mole) in 50 milliliters of ether was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then treated in the manner of Example I. The crude product was crystallized from ether to yield 10.7 grams of product (42%) as fine white needles, m.p. 99°-101° C. Analysis Calculated for C16H20N2O: C,74.96; H,7.86; N,10.93 Found: 75.19; 7.96; 10.88
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)([O-])=O.CC(O)=O>C1COCC1.[Zn]>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:21])[N:11]=[CH:10][CH:9]=[C:8]2[O:7][C:6]1[CH:5]=[C:4]([NH2:1])[C:24]([NH2:25])=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)c2cc1OC
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3ccc(N)c(N)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(3,4-Dinitrophenoxy)-6,7-dimethoxyquinoline (Step a, 0.256 g) was dissolved in THF (40 mL) and HOAc (1 mL) was added followed by zinc dust (1.3 g). Mixture was stirred at RT for 3 h and filtered through a Celite® pad. Solvent was evaporated and residue was washed with NaOH 1 M and extracted with EtOAc. The organic phase was dried, filtered and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.NC1C=CC=C2C=1CCC2.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>CCOCC.CCCCCC>[CH2:31]([NH:33][C:34]([NH:1][C:2]1[C:10]([C:11]([OH:20])([C:12]([F:13])([F:14])[F:15])[C:16]([F:17])([F:18])[F:19])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2)=[O:35])[CH3:32]
Reactant: CCN=C=O
Reactant: Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2c1CCC2
Agent: Nc1cccc2c1CCC2
Solvent: CCOCC
Solvent: CCCCCC
Product: CCNC(=O)Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2c1CCC2

Procedure:
To 4-amino-5-(hexafluoro-2-hydroxy-2-propyl)indan (4.2g, 14 mmole, prepared from 4-aminoindan by the procedure of Gilbert, J. Org. Chem., 30, 1001 (1965), m.p. 155°-8°) in 50 ml 4:1 Et2O-hexane add ethyl isocyanate (1.3 g, 18mmole). After 1 hour filter the solid and dry to give 4.4 g N-ethyl-N'-[5-(hexafluoro-2-hydroxy-2-propyl)-4-indanyl]urea; m.p. 142°-143° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27].[Br:28]N1C(=O)CCC1=O.ClCC(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]([Br:28])[C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)C(Br)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.9 %

Procedure:
A mixture of methyl 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetate (0.400 g, 0.00100 mol), N-bromosuccinimide (0.370 g, 0.00210 mol), benzoyl peroxide (0.0100 g) and tetrachloroethane is stirred 2.5 hours at reflux, cooled to room temperature, and chromatographed on silica gel with methylene chloride to afford the title compound as an off-white solid (0.430 g, 90.0%, mp 84-87° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccccc12

Procedure:
4-Quinazolone (5 g, 34.2 mmol), phosphorus pentachloride (10.26 g, 47.9 mmol) and phosphorus oxychloride (40 ml) were refluxed for two hours at 115-118 C. The phosphorus oxychloride was removed in vacuo and the residue was extracted in ether. The entire mixture was then poured into a vessel containing crushed ice and again extracted with ether. The ether layer was then washed with sodium bicarbonate and dried. The ether was then removed under reduced pressure and the crude material was recrystallized from hexanes to afford the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[CH2:10][N:11]2[C:15]3[C:16](=[O:34])[N:17]([CH3:33])[C:18]([CH:27]([OH:32])[C:28]([O:30]C)=[O:29])=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[C:14]=3[CH:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[Li+].[OH-]>C(OC(C)(C)C)(=O)C.O1CCCC1>[C:14]([O:32][CH:27]([C:18]1[N:17]([CH3:33])[C:16](=[O:34])[C:15]2[N:11]([CH2:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:35])[CH:12]=[CH:13][C:14]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:28]([OH:30])=[O:29])([CH3:19])([CH3:15])[CH3:13]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2ccn(CC(=O)Nc3ccc(F)cc3)c2c(=O)n1C
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)(C)C
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3CC(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An ice cold mixture of methyl 2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (20.5 mg, 0.043 mmol) in t-Butyl acetate (5.0 mL) was treated with perchloric acid (0.2 mL, 0.102 mmol) and then stirred at ambient temperature for 2 hours. The mixture was quenched with 3M NaOH and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate filtered and concentrated. The residue was dissolved in Methanol (1.000 mL) and Tetrahydrofuran (THF) (1.000 mL), treated with 1N LiOH (0.4 mL, 0.400 mmol) and then heated to 70° C. for 80 minutes. The mixture was concentrated and then purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to give the desired product as a light brown residue. 1H NMR (400 MHz, CHLOROFORM-d) ppm 10.54 (s, 1H), 7.62-7.44 (m, 3H), 7.36-7.14 (m, 4H), 7.07-6.91 (m, 2H), 6.09 (d, J=2.9 Hz, 1H), 5.50 (s, 1H), 5.22-5.16 (m, 1H), 5.15-5.08 (m, 1H), 3.76 (s, 3H), 2.44 (s, 3H), 1.00 (s, 9H); LC/MS (m/z) ES+=520 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:16](OC(OCC)(OCC)C)[CH3:17]>C(O)C>[CH3:16][C:17]1[N:6]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Product: Cc1nc2ccccc2c(=O)n1-c1nnn[nH]1

Procedure:
A mixture of 3.8 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide and 3.3 g of 1,1,1-triethoxyethane in 50 ml of ethanol was heated at reflux for 18 hours. The mixture was then concentrated to a small volume and the resulting solid was collected by filtration and air dried to give 2-methyl-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 225°-226° C. This compound has the following structural formula: ##STR5##
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:17]3[N:16]([C:17]4[CH2:18][CH2:19][CH2:20][N:16]=4)[CH2:20][CH2:19][CH:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: Clc1cccc2c1Sc1ccccc1N2
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccc2c1Sc1ccccc1N2C1=CCCN1C1=NCCC1
Yield: 17.1 %

Procedure:
A solution of 4-chlorophenothiazine (32.3 g., 0.134 mole) and 2-pyrrolidinone (23 g., 0.27 mole) in 125 ml. of 1,2-dichloroethane is added dropwise to a solution of phosphorus oxychloride (20.5 g., 0.134 mole) in 50 ml. of 1,2-dichloroethane in about 35 min. Isolation of the product from the reaction mixture according to the procedure of Example 1 provides 7.5 g., (17.1% yield) of 4-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE free base, m.p. 195°-197° C. Analytically pure 4-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE HYDROCHLORIDE obtained by crystallization from ethanol-ether has a melting point of 232°-234° C. (corr.).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>C(C1C=CC=CC=1)C>[C:1]1([CH2:8][CH:9]([O:16][CH:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCc1ccccc1
Product: c1ccc(CC(OC(Cc2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
Phenol (21.21 grams; 0.25 mole) and methylbenzyl alcohol (30.5 grams; 0.25 mole) in 100.00 grams of ethylbenzene were refluxed at a temperature of from about 135° to 140° C. for about four hours with 0.500 grams (0.33 weight percent) concentrated sulfuric acid. Water was removed overhead as a azeotrope and was collected in a Dean-Stark trap. Methylbenzyl alcohol conversion was quantitative but only 8% selectivity to α-phenylmethylbenzyl ether was obtained. The remaining product was styrene (74.8% selectivity) and styrene polymer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10](=[CH2:12])[CH3:11].C(Cl)Cl.FC(F)(F)S(O)(=O)=O>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]([CH3:12])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(C)C
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Oc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
4-Bromophenol(57.8 mmoles, 10.0 g) was added to a -30° C. solution of isobutylene (40 ml) and methylene chloride (50 ml) and then cooled to -78° C. Trifluoromethanesulfonic acid (4 mmoles, 0.35 ml) was added. The mixture was held at -78° C. for 4 hours and then allowed to warm to room temperature. Triethylamine (0.5 ml) was added; the solvent was removed. The residue was chromatographed over silica gel eluted with 1% ethyl acetate in hexane to yield 12.4 g. (MS)
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.BrCCC1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[C:32]([CH:35]=1)[C:33]#[N:34].CS(O[CH2:47][CH2:48][CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)(=O)=O>CN(C)C=O.O1CCCC1>[CH:50]1([CH2:49][CH2:48][CH2:47][N:39]2[CH2:40][CH2:41][N:36]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:35][C:32]=3[C:33]#[N:34])[CH2:37][CH2:38]2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: CS(=O)(=O)OCCCC1CCCCC1
Reactant: COc1ccc(N2CCNCC2)c(C#N)c1
Agent: BrCCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(CCCC3CCCCC3)CC2)c(C#N)c1
Yield: 46.6 %

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride, (2-bromoethyl)benzene and tetrahydrofuran were replaced with 5-methoxy-2-(piperazin-1-yl)benzonitrile (599 mg), 3-cyclohexylpropyl methylsulfonate (608 mg) and N,N-dimethylformamide (6.8 mL), respectively, and the resulting crude product was purified on silica gel column chromatograpy (eluent, ethyl acetate: hexane=1:1) to provide 2-[4-(3-cyclohexylpropyl)piperazin-1-yl]-5-methoxybenzonitrile (439 mg).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To a suspension of NaH (318 mg, 7.94 mmol) in THF (20 mL) was added a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.78 g, 7.94 mmol) in THF (5 mL) dropwise over 30 min at 0° C. After stirring for 10 min, a solution of 1-benzylpiperidin-4-one (1.0 g, 5.29 mmol) in THF (5 mL) was added dropwise at 0° C. over 20 min. The mixture was allowed to stir for 60 min. Then, the reaction was quenched with water (10 mL). The mixture was extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 25% of EA in PE as eluant to give the product (1.2 g, 87.3%) as a yellow oil. MS (ESI, m/e) [M+1]+ 260.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[OH-].[K+].[C:16]1([C:22](=[N:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([C:22](=[N:29][C@@H:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)N=C(c1ccccc1)c1ccccc1
Yield: 87.8 %

Procedure:
1-(Bromomethyl)-4-(trifluoromethoxy)benzene (28.1 g, 0.110 mol) and 50% potassium hydroxide (225 mL, 2.00 mol) were added to a toluene (1 L) suspension of tert-butyl [(diphenylmethylene)amino]acetate (29.5 g, 0.10 mol) and N-(9-anthracenylmethyl)cinchonidinium chloride (5.79 g, 0.01 mol) under ice-cooling with stirring. The mixture was vigorously stirred at the same temperature for 3.25 hours and then separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate (200 mL), and the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 20:1, 15:1, and 10:1, V/V) to give 41.2 g of the title compound (mixture of a yellow oil and a yellow solid, yield: 88%, optical purity: 88%).
Reaction SMILES: F[C:2]1C=CC(N2C(C(O)=O)=CN=C2SCC2C(F)=CC=C(F)C=2F)=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:38]([C:39]([O-:41])=[O:40])=[CH:37][N:36]=[C:35]2[NH:42][CH2:43][C:44]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=2[F:52])=[CH:30][CH:29]=1>C1COCC1.CO>[CH3:2][C:37]1[N:36]=[C:35]([NH:42][CH2:43][C:44]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=2[F:52])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[C:38]=1[C:39]([OH:41])=[O:40]
Reactant: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: O=C([O-])c1cnc(NCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(NCc2c(F)ccc(F)c2F)n(-c2ccc(F)cc2)c1C(=O)O

Procedure:
Methyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)amino)-1H-imidazole-5-carboxylic acid (69) was prepared in a similar manner as that described for the synthesis of compound 11 using 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)amino)-1H-imidazole-5-carboxylate (68) (60 mg, 0.158 mmol), 1NLiOH (5 mL) in THF (5 mL) and MeOH (5 mL).