Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C2C(C(F)(F)F)=CC(NC3C=NC=CC=3)=CC=2C2CNCCC12.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([NH:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][C:44]=3C(F)(F)F)=[CH:33][C:34]=2[C:36]#[N:37])[C@@H:29]2[CH2:49][NH:50][CH2:51][CH2:52][C@H:28]12.Br[C:54]1[C:55]([O:60]CC)=NC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:55]([O:60][C:40]1[C:39]([NH:38][C:32]2[CH:31]=[C:30]3[C:35](=[C:34]([C:36]#[N:37])[CH:33]=2)[N:27]([CH3:26])[C@H:28]2[CH2:52][CH2:51][NH:50][CH2:49][C@@H:29]32)=[CH:44][CH:43]=[CH:42][N:41]=1)[CH3:54]
Reactant: CCOc1ncccc1Br
Reactant: CN1c2c(C#N)cc(Nc3cnccc3C(F)(F)F)cc2[C@@H]2CNCC[C@@H]21
Agent: CN1c2c(cc(Nc3cccnc3)cc2C(F)(F)F)C2CNCCC21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ncccc1Nc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method B) as a yellow solid (30 mg, 28%) from (4aS,9bR)-8-amino-6-cyano-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylic acid tert-butyl ester (Example 162, 100 mg, 0.31 mmol), 3-bromo-2-ethoxypyridine (63 mg, 0.31 mmol) and Cs2CO3 (199 mg, 0.6 mmol). MS (ESI): 350 (base, M+H).
Reaction SMILES: [CH2:1]([C:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([C:10]#[N:11])[C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(O)C.[Ni]>[CH2:12]([C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:8][NH2:9])[CH2:10][NH2:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(C#N)(C#N)CCCCCC
Agent: [Ni]
Solvent: CCO
Product: CCCCCCC(CN)(CN)CCCCCC
Yield: 63.7 %

Procedure:
180.5 g (0.77 mol) of 2,2-dihexylpropanedinitrile was dissolved in 320 ml of ethanol. About 5 g of Raney nickel (dispersion in toluene) was added thereto, and the dinitrile was catalytically reduced at 100° C. under hydrogen pressure of 100 kg/m2 in an autoclave for 6 hours. The catalyst was removed, and ethanol was distilled off to obtain an oily material. The oily material was distilled under reduced pressure to obtain 119 g of the desired product as a colorless oil (boiling point: 153° to 160° C./4 mmHg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[Br:25][C:26]1[CH:27]=[C:28]([SH:32])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Br:25])[CH:27]=2)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Reactant: Sc1cccc(Br)c1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2cccc(Br)c2)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 3-bromothiophenol. Colorless oil (85%). MS (EI): 464.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=[C:12]([Cl:14])[N:13]=1>CO>[Cl:14][C:12]1[N:13]=[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ccsc2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2ccsc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Scheme 6 shows the synthesis of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 starting by cyclization of methyl 2-amino-thiophenecarboxylate 15 (95 g) with chlorosulfonyl isocyanate at low temperature remains (−60° C. to −55° C.) to give thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 16. Phosphorous oxychloride was added slowly to a cold solution of thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 16 and N,N-dimethylaniline (0.75 equiv.) in acetonitrile while maintaining the temperature below 25° C. The mixture was then heated to 80-85° C. and stirred for 24 hours to afford dichlorothieno[2,3-d]pyrimidine 17. Morpholine (2.2 equiv.) was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine 17 in methanol and stirred at ambient temperature for 1 h to give 18.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[S:26][C:25]5=[N:27][CH:28]=[C:29]([C:30]6[CH:31]=[C:32]([C:37]([F:40])([F:39])[F:38])[C:33]([NH2:36])=[N:34][CH:35]=6)[N:24]5[N:23]=4)[CH:20]=3)[NH:15][C:14]2=[O:41])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>CO>[O:41]=[C:14]1[C:11]2([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[S:26][C:25]4=[N:27][CH:28]=[C:29]([C:30]5[CH:31]=[C:32]([C:37]([F:38])([F:40])[F:39])[C:33]([NH2:36])=[N:34][CH:35]=5)[N:24]4[N:23]=3)[CH:20]=2)[NH:15]1.[ClH:42]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1ccc(-c3nn4c(-c5cnc(N)c(C(F)(F)F)c5)cnc4s3)cc12
Agent: Cl
Solvent: CO
Product: Nc1ncc(-c2cnc3sc(-c4ccc5c(c4)C4(CCNCC4)C(=O)N5)nn23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-[2-(1′-(tert-butoxycarbonyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-trifluoromethyl-pyridin-2-ylamine (6.4 mg, 0.011 mmol) and HCl (4N in dioxane, 0.03 mL, 0.11 mmol) in MeOH (0.2 mL) was stirred at room temperature for 16 h. The solvent was evaporated under vacuum and the residue was triturated from Et2O to give the desired product as HCl salt (5 mg, 86%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.01 min, [M+H]+ m/z 486.1; 1H NMR (300 MHz, D2O) δ 8.19 (m, 1H), 8.04 (m, 1H), 7.31 (m, 3H), 6.56 (m, 1H), 3.49 (m, 2H), 3.21 (m, 2H), 3.10 (m, 2H), 1.92 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.CO.C(O)(=O)C>[Pd].C1COCC1>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Reaction time: 24 h

Procedure:
40 mg of 5% palladium on carbon were added to a solution of 416 mg (1.3 mmol) of 3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-acrylic acid in 20 ml of THF, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 24 h. Then 10 ml of methanol and 40 mg of 5% palladium on carbon were added, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for further 24 hours. Then 10 ml of acetic acid were added, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for another 24 h. The mixture was filtered and evaporated under reduced pressure. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 400 mg.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.O.S(Cl)([Cl:21])=O>C(OCC)C.[Cl-].[Na+].O>[Cl:21][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCCc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: ClC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A 1 liter 3-necked flask equipped with a condenser, electronic thermocouple, mechanical stirrer and under a nitrogen atmosphere was charged with 1,2,3,4-tetrahydro-1-naphthol (34.3 g; 0.23 mol) in dry diethyl ether (420 ml). Pyridine (4.7 ml) was added and the flask was cooled to 16° C. in a bath of water and ice. A solution of thionyl chloride (50.7 ml; 0.70 mol) in ether (140 ml) was then added dropwise in 25 minutes and stirring continued overnight while allowing the bath to warm to ambient temperature. The reaction mixture was then poured into cold brine (400 g ice and 800 ml brine) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (2×150 ml) and the combined organic extract was dried with sodium sulphate. Filtration and removal of solvent in vacuo gave 1,2,3,4-tetrahydro-1-chloronaphthalene (36.9 g) as an oil. This material was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1.CC(C)([O-])C.[Na+]>>[CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][N:12]2[C:19]1[CH:18]=[N:17][C:16]([Cl:15])=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cn1
Reactant: c1ccc(CN2C[C@H]3NCC[C@H]32)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Clc1ccc(N2CC[C@@H]3[C@H]2CN3Cc2ccccc2)cn1
Yield: 84 %

Procedure:
The product from Example 51E (0.26 g, 1.0 mmol) and 2-chloro-5-iodopyridine were processed according to the procedure described in Example 1A, except that a larger amount of sodium tert-butoxide (0.384 g, 4.0 mmol) was used. The crude product was purified by chromatography on SiO2 (dichloromethane:methanol, 95:5) to provide the title compound (0.25 g, 84%). MS (DCI/NH3) m/z 300/302 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH:10](Br)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CN(C)C=O>C(N(CC)CC)C>[CH2:1]([O:8][C:9](=[O:16])[CH:10]([O:25][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)CC(Br)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(OC(=O)c1ccncc1)C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A total of 29.5 g of benzyl-(RS)-α-bromo-isocaproate was added dropwise at 60° with stirring over a period of 15 minutes to a solution of 12.8 g of isonicotinic acid in a mixture of 60 ml. of dimethyl-formamide and 14.8 ml of triethylamine. The reaction mixture was stirred for 5 hours at 90°. The triethylamine hydrobromide was then filtered off by suction and the filtrate evaporated under reduced pressure at 60°. The residue was dissolved in 100 ml of ethyl acetate and filtered and the filtrate washed three times with 15 ml portions of 1-N potassium bicarbonate solution and twice with 20 ml portions of water. The ethyl acetate solution was dried with magnesium sulphate and evaporated under reduced pressure at 45°. Benzyl-(RS)-2-(isonicotinoyloxy)-isocaproate was obtained as an oil.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[H-].[Na+].B(OCC)(OCC)OCC.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1F)([O-:24])=[O:23]>CN(C)C=O>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1cccc(O)c1O
Agent: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1cccc(O)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
18.9 g of pyrogallol, 380 ml of anhydrous dimethylformamide and 13.6 g of sodium hydride in suspension at 53% in oil were mixed together under an inert gas atmosphere and then stirred for 45 minutes at ambient temperature. 29 ml of triethyl borate were added, and the mixture was stirred for 30 minutes. Then, 17.6 ml of 2-nitro fluorobenzene were added over one hour at 0° C. followed by stirring for 20 hours at ambient temperature. The mixture was poured into a water-ice-N hydrochloric acid mixture and the precipitate was separated, washed with petroleum ether, taken up in ethyl ether and washed with N hydrochloric ac:id to obtain about 27 g of the expected product (Yield approx.: 76%) in the form of beige crystals.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])([CH3:14])[NH:13][C:7]2=[CH:6][CH:5]=1.[C:17]([OH:20])(=[O:19])[CH3:18]>>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])([CH3:14])[NH:13][C:7]2=[CH:6][CH:5]=1.[C:17]([O-:20])(=[O:19])[CH3:18]
Reactant: CC(=O)O
Agent: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Product: CC(=O)[O-]
Temperature: 25 °C

Procedure:
100 g of ethoxyquin and 153.4 g of glacial acetic acid were mixed with stirring at room temperature. Hereby was obtained a 50% by weight solution of ethoxyquin acetate in glacial acetic acid. The solution had a viscosity of 60 cps at 20° C.
Reaction SMILES: OO.[CH3:3][C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:23]=[CH:22][C:14]3S[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1.[S:24](=[O:28])(=O)(O)[OH:25]>C(O)(=O)C.C(Cl)Cl.CO>[O:25]=[S:24]1(=[O:28])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:16][C:17]=2[C:13]2[CH:12]=[C:11]([NH:10][C:7]3[N:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=3)[CH:23]=[CH:22][C:14]1=2
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(Nc2ccc3sc4ccccc4c3c2)nn1
Agent: OO
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(Nc2ccc3c(c2)-c2ccccc2S3(=O)=O)nn1
Temperature: 60 °C

Procedure:
Hydrogen peroxide (100 vols, 1 ml) was added to 2-(6-methylpyridazin-3-ylamino)dibenzothiophene (Example 74; 300 mgs, 1.03 mmol) in acetic acid (3 ml) and conc. sulphuric acid (0.1 ml) and the mixture was heated to 60° C. for 40 minutes. On cooling to room temperature the mixture was diluted with DCM:MeOH (1:19) washed with aqueous potassium carbonate, dried over sodium sulphate and concentrated. Chromatography (eluent gradient of DCM to DCM:MeOH(1:1)) gave the product as an off white solid (0.131 g). NMR: 9.87 (brs, 1H), 8.48 (brs, 1H), 8.00-7.70 (m, 5H), 7.65 (t, 1H), 7.45 (d, 1H), 7.20 (d, 1H), 2.52 (s, 3H); m/z 324.28.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][O:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31]CC4C=CC(OC)=CC=4)=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:3][CH2:2]1.COC1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2ccc([C@H]3CC[C@H](OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc2)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc([C@H]2CC[C@H](OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Reaction time: 2 h

Procedure:
Trans-5-cyclopropyl-3-(2,6-dichloro-phenyl)-4-{4-[4-(4-methoxy-benzyloxy)-phenyl]-cyclohexyloxymethyl}isoxazole (1.33 mmol, 770.00 mg) in dichloromethane (17 mL) is treated at room temperature with methoxybenzene (13.3 mmol, 1.45 mL) and trifluoroacetic acid (8.5 mL). The solution is stirred for 2 h and concentrated under reduced pressure. The residue is co-evaporated with CCl4 (2×) and triturated with hexanes. The crude product is supported on silica gel and purified by flash chromatography (120 g silica) eluting with a gradient of 20-50% EtOAc in hexane to give the title compound (544 mg, 89%) as a white solid. MS m/z 458.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:14].[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[O:14][CH2:15][CH:17]1[O:19][CH2:18]1
Reactant: BrCC1CO1
Reactant: Oc1cccc(N2CCCCC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1c(OCC2CO2)cccc1N1CCCCC1
Yield: 84.7 %

Procedure:
A mixture of 7.47 grams of 2-chloro-3-piperidinophenol, 29.00 grams of epibromohydrin, 28.79 grams of potassium carbonate and 400 ml of acetonitrile is heated to reflux for twenty hours, insoluble matters are removed therefrom by filtration, the filtrate is entirely concentrated to dryness, and the residue is purified by a silica gel chromatography followed by recrystallization from n-hexane to give 8.0 grams (85%) of 1-(2-chloro-3-piperidinophenoxy)-2,3-epoxypropane as colorless crystals of m.p. 55°-57° C. NMR (CDCl3): δ 1.55-1.95 (m, 6H), 2.75-3.19 (m, 7H), 4.10 (dd, 1H, J=11 Hz and 14 Hz), 4.18 (dd, 1H, J=11 Hz and 21 Hz), 6.54-6.77 (m, 2H). Elementary analysis calculated as C14H18ClNO2 : C 62.80, H 6.78, N 5.23, Cl 13.24; Found: C 62.61, H 6.87, N 5.08, Cl 13.15.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14](O)=[C:13]([Cl:18])[CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]([NH2:10])[CH:16]=[CH:15][C:14]=1[O:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Cc1cccc(CO)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(COc2ccc(N)cc2Cl)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of (6-methyl-pyridin-2-yl)-methanol (280 mg, 2.29 mmol), 4-amino-2-chloro-phenol (359 mg, 2.5 mmol) and triphenylphosphine (0.655 mg, 2.5 mmol) in THF (8 ml) was added DIAD (0.49 ml, 2.5 mmol) and the mixture was stirred at rt for 20 h. The mixture was concentrated in vacuo, diluted with 1N HCl (30 ml), washed with EtOAc (3×20 ml) and basified to pH 12 by 1N NaOH. The mixture was extracted with EtOAc (4×40 ml); the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 15A (?? mg, ??% pure)
Reaction SMILES: [C:1](Cl)(=[O:17])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH3:20][C:21]1([CH3:30])[CH2:26][CH:25]([OH:27])[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22]1.[OH-].[Na+]>ClCCl.O>[C:1](=[O:17])([O:27][CH:25]1[CH2:26][C:21]([CH3:30])([CH3:20])[NH:22][C:23]([CH3:29])([CH3:28])[CH2:24]1)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCOC(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCOC(=O)OC1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.7 g (0.1 mol) of tetradecyl chlorocarbonate are added slowly to a solution of 19.4 g (0.1 mol) of 2,2,6,6-tetramethyl-4-piperidinol hydrochloride in 150 ml of dichloromethane, maintaining the temperature at between 0° C. and 5° C. After the end of the addition, the mixture is stirred for 2 hours at ambient temperature, and a solution of 8.8 g (0.22 mol) of NaOH in 50 ml of water is then added slowly, with cooling to -10° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[C:13]2=[O:23])[CH:6]=1)[CH3:2].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][O:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][N:12]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=3[CH3:11])[C:4]([NH:3][CH2:1][CH3:2])=[O:24])[C:13]2=[O:23])=[CH:18][CH:17]=1
Reactant: CN(C)CCCl
Reactant: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(O)cc3c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(OCCN(C)C)cc3c2=O)c1

Procedure:
N-Ethyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (88 mg), 2-dimethylaminoethyl chloride hydrochloride (51 mg), potassium carbonate (0.38 g), and sodium iodide (3 mg) were stirred in acetone (4 ml) at 60° C. for 17 hours. The reaction mixture was filtered, the solids washed with acetone, and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 2N NaOH solution, brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica-column eluting with 10% methanol/ethyl acetate+1% aqueous ammonia solution gave 3-[7-[2-(dimethylamino)ethoxy]-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide as a white solid; NMR Spectrum: (DMSOd6) 1.11 (t, 3H), 2.10 (s, 3H), 2.24 (s, 6H), 2.68 (t, 2H), 3.28 (m, 2H), 4.18 (m, 2H), 6.72 (d, 1H), 7.21 (d, 1H), 7.41 (d, 1H), 7.50 (d, 1H), 7.69 (s, 1H), 7.71 (d, 1H), 7.78 (s, 1H), 7.89 (d, 1H), 8.48 (s, 1H); Mass Spectrum: M+H+ 394.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:30][CH2:29][CH:28]([O:27][C:26]5[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=5)[CH2:33][CH2:32]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-fluoro-phenoxy)-piperidine (Table No.1, SM 5) in ethanol essentially as described above in Example 21. Purity by LC/MS=88%, [M+H]+=481.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:6]=[N:5]1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][CH2:2][CH2:3][N:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][CH:10]=2)[N:6]=[N:5]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nnn(CCF)n2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FCCn1nnc(-c2ccc(CBr)cc2)n1
Reaction time: 5 h
Yield: 15.9 %

Procedure:
Under a light source a stirred solution of 2.8 grams (0.013 mole) of 1-(2-fluoroethyl)-4-(4-methylphenyl)-1,2,3,5-(1H)-tetrazole, 2.4 grams (0.013 mole) of N-bromosuccinimide, and 0.19 gram (0.0008 mole) of benzoyl peroxide in 100 mL of carbon tetrachloride was heated to reflux. Once at reflux the reaction mixture was stirred for five hours. After this time the heat source was removed and the reaction mixture was stirred for about 18 hours. At the conclusion of this period the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 0.59 gram of 4-[1-(2-fluoroethyl)-1,2,3,5-(1H)-tetrazol-4-yl]benzyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:4]=1[CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1)[CH3:2].C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:3]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:4]=1[CH2:5][C:6]1[NH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCc1c(F)ccc(F)c1CC1=NCCN1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1c(F)ccc(F)c1Cc1ncc[nH]1

Procedure:
2-(2-Ethyl-3,6-difluoro-benzyl)-1H-imidazole was prepared from 2-(2-ethyl-3,6-difluoro-benzyl)-4,5-dihydro-1H-imidazole (Example 199), TCCA and DBU in analogy to Example 194e): light yellow crystals; MS (ISP): 223.3 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[CH2:15]([O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=1)[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Oc1cccc(C(F)(F)F)n1
Reactant: CC(C)(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(trifluoromethyl)pyridin-2-ol (5.00 g, 30.7 mmol) in dry DMF (50 mL) was added NaH (3.71 g, 92.1 mmol) under N2 and the mixture was stirred at rt for 1 h. Then 1-bromo-2,2-dimethylpropane (11.6 g, 76.7 mmol) was added and the resulting mixture was heated at 100° C. overnight, cooled, quenched with water (10 mL) and extracted with EA twice. The combined organic layers were washed with brine (3×), concentrated and purified by CC on NH silica gel (PE/EA=100/1) to give compound P12a (1.05 g, 15%) as an oil.