Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]Cl.CN(C)C=O>C(OCC)(=O)C>[CH2:32]1[C:27]2[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:1]1[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1
Reactant: ClCc1ccccc1CCl
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cn2cc(Oc3cccc(N4Cc5ccccc5C4)c3)ccc2n1)C1CC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 34 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (19.4 mg, 0.063 mmol), 1,2-bis(chloromethyl)benzene (13.5 mg, 0.077 mmol) and N,N-dimethylformamide (2.0 mL) was stirred at 50° C. for 14 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (8.8 mg, 34%).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1.[C:8](=O)([O-])[O-].[K+].[K+].[C:14](#[N:16])[CH3:15]>O.C(#N)C=C>[OH:7][C@@H:4]1[CH2:5][CH2:6][N:2]([CH2:8][CH2:15][C:14]#[N:16])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: O[C@@H]1CCNC1
Reactant: CC#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C=CC#N
Product: N#CCCN1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-(−)-3-pyrrolidinol hydrochloride (Tokyo Kasei Kogyo Co., Ltd.) (50 g) and potassium carbonate (55.8 g) were dissolved in a mixed solvent of acetonitrile (500 mL) and water (100 mL), and acrylonitrile (29 mL) was added dropwise to the solution at room temperature. Subsequently, the mixture was stirred overnight at room temperature. After the completion of the reaction, the solvent was concentrated, and the obtained residue was dissolved in water. Potassium carbonate was added to saturation. The mixture was extracted 3 times with chloroform, and the extract was dried over potassium carbonate. The solvent was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give (R)-3-(3-hydroxypyrrolidin-1-yl)propionitrile (53 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[OH-].[Na+].O>C1(C)C=CC=CC=1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40° C. After the temperature had dropped to 30° C., the reaction mixture was heated to 45-50° C. using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 NH2SO4 (200-300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2×300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 165.0 (d, 1JCF=259.6 Hz), 152.3 (d, 3JCF=13.1 Hz), 128.2 (d, 3JCF=11.9 Hz), 122.4 (d, 1JCF=273.4 Hz), 110.1 (d, 2JCF=22.5 Hz), 105.9 (q, 1JCF=242.6 Hz), 104.3 (d, 2JCF=26.1 Hz), 67.6 (q, 1JCF=36.7 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-:16].[Na+]>Cl>[CH3:15][S:14][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CSc1nccc(-c2ccnc(F)c2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Temperature: 25 °C
Yield: 49 %

Procedure:
A suspension of 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 30.9 mmol) in 2N HCl (100 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and placed in an ice bath. The pH was adjusted to about 7 with 2N NaOH (about 100 mL). The resulting solids were collected by filtration, washed with water and dried to give 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (5.07 g) as a solid. This material was placed in the thimble of a Soxhlet apparatus and was attached to a 1 L flask charged with ethyl acetate (500 mL). The material was continuously extracted for 3 days. The resulting white precipitate from the ethyl acetate layer was collected by filtration (3.3 grams, 49% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.85 (br, s, 1H), 8.75 (d, J=5.0 Hz, 1H), 7.79 (d, J=5.0 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.13 (s, 1H), 6.86 (d, J=7.0 Hz, 1H), 2.58 (s, 3H); m/z (APCI-pos) M+1=220.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>CCO.CCO.CCO.CCO.[Ti].C(O)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:8][C:7]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: OCc1ccccc1
Solvent: CCO
Product: O=C(OCc1ccccc1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 6 h

Procedure:
A mixture of 3.59 g (10 mmol) of tert.butyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 1.5 g (6 mmol) of tetraethyl orthotitanate and 30 ml of benzyl alcohol is stirred at 130° for 6 hours, a small amount of solvent being distilled off in vacuo twice. The mixture is subsequently evaporated in a high vacuum, the residue is taken up in 40 ml of chloroform, the solution is treated with 40 ml of concentrated hydrochloric acid/water (1:1) and the mixture is stirred until both phases are clear. The chloroform solution is washed successively with 20 ml of 1N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to dryness. The residue is crystallized from ethyl acetate and there is obtained benzyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 180°-182°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:32]1[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 81 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 81%). 1H NMR (300 MHz, CDCl3): δ 2.54 (s, 3H), 3.50 (s, 4H), 3.79 (s, 4H), 4.15 (s, 3H), 6.89 (d, J=9.0 Hz, 2H), 7.31-7.50 (m, 2H), 7.65-7.75 (m, 2H), 7.90 (d, J=8.7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:14]1([S:24](Cl)(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.S(Cl)(Cl)(=O)=O.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([S:24]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)(=[O:26])=[O:25])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Clc1cccnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(c1cccc2ccccc12)N1CCN(c2ncccc2Cl)CC1
Yield: 70 %

Procedure:
Sulfonylation of 1-(3-chloropyridin-2-yl)piperazine (316 mg, 1.6 mmol) with naphthalene-1-sulfonyl chloride (362.7 mg, 1.6 mmol) was carried out according to a similar procedure described for example 2A (Except sulfonyl chloride was added before diisopropylethylamine) using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (1.4 mL, 8.0 mmol) as base. 1-(3-chloropyridin-2-yl)-4-(1-naphthylsulfonyl)piperazine was obtained in 70.0% yield (434.0 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C@H:12]1[CH2:14][O:13]1)[CH2:6][CH2:5]2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([CH2:15][N:22]=[CH:14][C@H:12]([C@@H:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[O:8]2)[OH:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Fc1ccc2c(c1)CC[C@@H]([C@H]1CO1)O2
Reactant: NCc1ccccc1
Solvent: CO
Product: O[C@H](C=NCc1ccccc1)[C@@H]1CCc2cc(F)ccc2O1
Yield: 65.1 %

Procedure:
(S)-6-fluoro-3,4-dihydro-2-((R)-oxiran-2-yl)-2H-chromene (30 mg, 0.154 mmol) was dissolved in methanol (2 ml) and kept under stirring. benzylamine (40 mg, 0.374 mmol) was added and the reaction mixture left to stir. After checking the reaction outcome, the solution was concentrated under reduced pressure and the crude residue further dried at 30° C. in vacuo to furnish 30 mg of (R)-2-(phenylmethylimino)-1-((S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol as a white solid (64% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][CH3:5].C1(C)C=CC=CC=1.[CH2:13]([P:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>CCCCCC>[Br-:1].[CH2:13]([P+:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:2][CH2:3][O:4][CH3:5])[CH3:14]
Reactant: CCP(CC)CC
Reactant: COCCBr
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC[P+](CC)(CC)CCOC
Product: [Br-]
Yield: 97 %

Procedure:
73 g (0.5 moles) of 2-bromoethylmethyl ether (a reagent available from Tokyo Chemical Industry Co., Ltd.) was added dropwise in 236 g (0.5 moles) of a 25% toluene solution of triethylphosphine (HISHICOLIN (registered trademark) P-2, a trade name of Nippon Chemical Industrial Co., Ltd.), and the mixture was allowed to react at 70 to 80° C. for 6 hours. After completion of the reaction, hexane was added for crystallization, thereby obtaining 125 g (percent yield: 97%) of a crystal of triethyl(2-methoxyethyl) phosphonium bromide. 33 g (0.3 moles) of sodium borofluoride (a reagent available from Kanto Chemical Co., Inc.) was added to 77 g (0.3 moles) of this triethyl (2-methoxyethyl)phosphonium bromide, and the mixture was allowed to react in an aqueous system. Subsequently, the reaction mixture was stirred for aging at room temperature for 3 hours. After completion of stirring, a product was completely dehydrated at 100° C. and at a degree of vacuum of 0.5 kPa, to which was further added 100 mL of dry methylene chloride, and a precipitate was filtered. This filtrate was concentrated and dried in vacuo at 100° C. and at a degree of vacuum of 0.5 kPa for 5 hours. Confirmation of the thus obtained product was carried out by means of 1H-NMR, 13C-NMR, 31P-NMR and 19F-NMR. A yield of the product (colorless transparent liquid) was 60 g (percent yield: 76%), and it was confirmed by 31P-NMR that its purity was 98% or more.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1c(O)ccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
4-Allyl-1H-indol-5-ol (Example 54, 2.67 g, 15.4 mmol), benzyl bromide (2.90 g, 17.0 mmol), and Cs2CO3 (6.03 g, 18.5 mmol) were combined in DMF (50 mL), and water (15 drops) was added. After stirring for 12 h at rt, the reaction mixture was concentrated under reduced pressure. The residue was taken up in water, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:7) gave 3.3 g (82%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.74 (d, 2H), 5.00 (d, 1H), 5.09 (d, 1H), 5.10 (s, 2H), 6.07 (m, 1H), 6.55 (s, 1H), 6.98 (d, 1H), 7.20 (m, 2H), 7.31 (m, 1H), 7.38 (m, 2H), 7.48 (m, 2H), 8.03 (br, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[C:21]1(=O)[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:21]1([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC2CCN(C3CCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (4.8 g), cyclobutanone (3.81 ml) and triethylamine (4.7 ml) were stirred in DCM (200 ml) at room temperature. After 10 min sodium triacetoxyborohydride (7.2 g) was added and the reaction was stirred at room temperature overnight. The reaction mixture was evaporated and redissolved in dichloromethane (50 ml). After washing with saturated potassium carbonate solution (2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml) and saturated brine (50 ml) the organic phase was dried (MgSO4) and evaporated to give the title compound (D5) as a colourless solid (5.72 g).
Reaction SMILES: C([O:5][P:6]([O:13][CH2:14][C:15]([NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:38])[O:36][CH3:37])=[CH:30][CH:29]=2)=[C:23]([NH:39][C:40]2[C:41]3[CH:49]=[CH:48][C:47]([CH:50]([CH3:52])[CH3:51])=[N:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH:22]=1)=[O:20])([CH3:17])[CH3:16])([O:8]C(C)(C)C)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+:64]>C(Cl)Cl>[P:6]([O-:7])([O-:8])([O:13][CH2:14][C:15]([NH:18][C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([O:36][CH3:37])=[O:38])=[CH:30][CH:29]=2)=[C:23]([NH:39][C:40]2[C:41]3[CH:49]=[CH:48][C:47]([CH:50]([CH3:51])[CH3:52])=[N:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH:22]=1)([CH3:17])[CH3:16])=[O:5].[Na+:64].[Na+:64]
Reactant: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(C)COP(=O)([O-])[O-])cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Yield: 92.2 %

Procedure:
The product of Example 441E (240 mg., 0.32 mmol) in CH2Cl2 (1.6 ml.) was reacted with TFA (1.6 ml.) at room temperature for 30 min. The reaction was concentrated, redissolved in water (4 mL) and treated with solid NaHCO3 (270 mg., 3.2 mmol) with stirring. The solution was purified on a C-18 column eluted with a gradient of methanol in water (0-100%). to give the title compound (202 mg., 92%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.17-1.40 (m, 12 H) 2.98-3.11 (m, 1 H) 3.66 (s, 3 H) 6.65 (s, 1 H) 7.18-7.27 (m, 1 H) 7.32 (d, J=8.09 Hz, 2 H) 7.48 (d, J=8.09 Hz, 2 H) 7.51-7.62 (m, 1 H) 7.94 (s, 1 H) 8.18-8.29 (s, 1 H) 8.77 (s, 1 H) 9.84 (s, 1 H)
Reaction SMILES: [C:1]([NH:5][CH2:6][C@H:7]([OH:10])CO)([CH3:4])([CH3:3])[CH3:2].[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:19]1C=CC=CC=1>O>[C:1]([N:5]1[CH2:6][CH:7]([OH:10])[O:18][C@@:11]1([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)NC[C@H](O)CO
Reactant: c1ccccc1
Solvent: O
Product: CC(C)(C)N1CC(O)O[C@@]1(C)c1ccccc1

Procedure:
22 g of (S)-1-tert.butylamino-2,3-dihydroxypropane, 20.7 g of benzaldehyde and 46 cc of benzene are heated at reflux in a water separator for 16 hours. The benzene and benzaldehyde are removed by distillation and the residue is distilled in a high vacuum. (S)-3-tert. butyl-5-hydroxy-methyl-2-phenyloxazolidine is obtained as yellowish oil (B.P. 110°-125° at 0.01 mm of Hg); [α]20546 = 17.8° (c = 1.99; chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: C1COCCN1
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Yield: 49 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and morpholine according to the procedure of example 25. Yield: 49%; MS: m/z=401 (M+H).
Reaction SMILES: C1COCC1.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:41]1[CH2:46][CH2:45][CH:44]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1>O>[O:9]1[CH2:10][CH2:11][CH2:12][O:7][CH:8]1[CH2:13][CH2:14][CH:41]1[CH2:42][CH2:43][CH:44]([CH:47]2[CH2:48][CH2:49][CH:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:62])([F:63])[F:64])=[CH:57][CH:56]=3)[CH2:51][CH2:52]2)[CH2:45][CH2:46]1
Reactant: O=C1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Reactant: c1ccc([PH](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(CCC2CCC(C3CCC(CCC4OCCCO4)CC3)CC2)cc1
Reaction time: 3 h
Yield: 41.9 %

Procedure:
THF (70 ml) was added to 1,3-dioxan-2-ylethyltriphenylphosphinebromide (6.80 g, 14.9 mmol), followed by adding to the mixture, potassium-t-butoxide (1.68 g, 14.9 mmol) at 0° C., stirring the mixture at the same temperature for 3 hours, dropwise adding to the reaction solution, a 10 ml THF solution of the above 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane (2.7 g, 7.7 mmol), stirring the mixture at the same temperature for one hour, further stirring at room temperature for 3 hours, adding water (50 ml) to the reaction solution, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the resulting residue according to column chromatography treatment using heptane/ethyl acetate (3/1) as a developing solvent, on silica gel, distilling off the solvent, hydrogenating the residue (3.2 g) in the presence of a catalyst of 5% Pd/C (0.15 g), in ethanol solvent, filtering off the catalyst distilling off the solvent under reduced pressure, and recrystallizing the residue from heptane/ethanol (5/1), to obtain 4-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane (1.46 g, 3.23 mmol). The yield of this product from 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane was 42%.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:26]=[C:25]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:33]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:23]2[CH:24]=[C:25]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])[CH:26]=[CH:21][C:22]=2[CH3:33])[CH:11]=1)#[N:16]
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1Br
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)C(C)C)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-bromo-4-(isopropylsulfonyl)-1-methylbenzene (Intermediate 64), the title compound was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:20][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]3[S:10][C:11]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=4[N:13]=3)=[C:6]([Cl:19])[CH:5]=2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)(=[O:23])[CH3:22]
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Cl)c(Oc3nc4ccc(Cl)cc4s3)c(Cl)c2)cc1

Procedure:
4-Acetyl-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide was synthesized (36%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-acetyl-benzenesulfonyl chloride (Fluka) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (br s, 1H), 8.18 (dd, J=7.8, 1.7 Hz, 2H), 8.15 (d, J=2.2 Hz, 1H), 8.01 (d, J 7.8, 1.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.32 (s, 2H), 2.63 (s, 3H). MS (EI): m/z 525 (M−H).
Reaction SMILES: O1COCO[CH2:2]1.[CH:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[ClH:24]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[Cl:24][CH2:2][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: Cl
Reactant: FC(F)(F)c1ccc(Cc2ccccc2)cc1
Reactant: C1OCOCO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(Cc2ccc(CCl)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
In a 250 ml of round-bottom three-necked flask, 0.68 g of zinc chloride (dried for 3 hours under vacuum at 100° C.); 4.0 g of 1,3,5-trioxane; 16.0 g of 4-trifluoromethyldiphenylmethane and 4.5 ml of 100% acetic acid are combined, heated to 60° C. and dried halogen chloride gas is introduced. The result is a two phase system that turns brown. HCl was introduced for a total of 3 hours. Following 6 hours of reaction time, the conversion is d.c. controlled (developing agent: petroleum benzin 60°-80° C., result: no conversion, starting material). Once again 0.68 g of ZnCl2 and 2.0 g of 1,3,5-trioxane are added to the reaction mixture and stirred overnight. The reaction mixture was stirred for a total of 30 hours at 60° C., whereby following dc result, approximately 20% of the desired compound formed. The mixture was cooled to room temperature and diluted with 150 ml of diethyl ether. The ether solution was washed to neutral several times with a total of 2.5 liters of water. The organic phase was shaken once with 80 ml of a saturated sodium hydrogen carbonate solution and then washed to neutral 2 times with 90 ml of water each time. The organic phase was dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated in a rotary evaporator (30° C., water-jet vacuum).