Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[Cl:8][C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(OCC)C>[Cl:8][C:9]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(OC(=O)Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a mixture of 1,1,1-trifluoro-2-propanol (114.1 mg, 1.0 mmol, Matrix Scientific) and triphosgene (98 mg, 0.33 mmol, Aldrich) in ethyl ether (10 mL) at −40° C. was added pyridine (80 μL, 1.0 mmol, EMD) in ethyl ether (1.0 mL) dropwise. The reaction mixture was warmed to 0° C. and stirred for 6 h. The flask containing the above reaction mixture was put into a refrigerator overnight and then filtered. The filtrate was concentrated in vacuo in ice both to colorless oil which was used directly in the next step.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:18]=[C:17]([CH:19]=C)[CH:16]=[CH:15][C:14]=3[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:11]=2)[C:6]([CH3:29])([CH3:28])[CH2:5][C:4]1=[O:30])[CH3:2].CSC.B.[OH-:35].[Na+].OO>C1COCC1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:18]=[C:17]([CH2:19][OH:35])[CH:16]=[CH:15][C:14]=3[O:21][CH2:22][C:23]([F:24])([F:25])[F:26])[CH:11]=2)[C:6]([CH3:28])([CH3:29])[CH2:5][C:4]1=[O:30])[CH3:2]
Reactant: [OH-]
Reactant: C=Cc1ccc(OCC(F)(F)F)c(-c2cc3c(cc2C)C(C)(C)CC(=O)N3CC)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(CO)ccc3OCC(F)(F)F)cc21
Reaction time: 8 h

Procedure:
To a solution of Compound 55A (0.24 mmol, 0.1 g) in 2 mL THF was added a solution of borane dimethylsulfide in THF (0.36 mmol, 0.03 mL) at 0° C. and the reaction mixture was stirred overnight. A solution of 2M NaOH (1 mL) was then added followed by a dropwise addition of hydrogen peroxide (30%, 1 mL). The solution was stirred at r.t. for 3 h. It was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The LCMS indicated the presence of the desired product (m/z found 436) and a byproduct where the amide carbonyl group was reduced to a methylene group (m/z found 422). The residue was purified by column chromatography (3:1 hexane/EtOAc followed by 1:1 hexane/EtOAc) to obtain 1-ethyl-7-[5-hydroxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,4,6-trimethyl-3,4-dihydro-1H-quinolin-2-one as a colorless oil (0.073 g).
Reaction SMILES: [CH2:1]([CH:7](O)[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.C([O-])(=[O:17])C.[Na+]>C(O)(=O)C>[CH2:1]([CH:7]1[CH:8]([OH:12])[CH:9]=[CH:10][C:11]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)[O-]
Reactant: CCCCCCC(O)c1ccco1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCC1C(=O)C=CC1O

Procedure:
In an autoclave, there were charged α-n-hexylfurfuryl alcohol (I-4) (18.2 g), water (910 g) and a buffer solution (0.6 g) comprising sodium acetate and acetic acid adjusted to pH 4.7. The resultant mixture was stirred at 110° C. under a nitrogen stream. After completion of the reaction, the reaction mixture was cooled and extracted with toluene. Removal of toluene from the extract gave a mixture (15.65 g) of 2-n-hexyl-3-hydroxy-4-cyclopentenone (II-4) and 2-n-hexyl-4-hydroxy-2-cyclopentenone (III-4). Yield, 86%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:26])[F:27])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N)n1
Yield: 46 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-trifluoromethyl-phenylamine provided the title compound (46% yield). 1H NMR (DMSO-d6) δ 2.36 (s, 3H, CH3), 6.17 (s, 1H, Ar), 6.54 (s, 2H, NH2), 7.32 (d, 1H, J=8.3 Hz, Ar), 7.38 (dd, 1H, J=8.1 Hz, J—2.3 Hz, Ar), 7.43 (d, 1H, J=2.1 Hz, Ar), 7.61 (d, 2H, J=8.7 Hz, Ar), 8.00 (d, 2H, J=8.5 Hz, Ar), 9.63 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)(=[O:28])=[O:27])[C:5]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:18]C(=O)C(C)(C)C)=[O:9])=[N:6][CH:7]=1.C([O-])(O)=O.[Na+]>CC(O)=O.Cl>[NH2:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[C:8]([C:5]1[C:4]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)(=[O:28])=[O:27])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: COc1cccc(NC(=O)C(C)(C)C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(N)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of N{-2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-3-methoxy-phenyl}-2,2-dimethyl-propionamide (105 mg, 0.17 mmol) in AcOH (6 mL) and 2 M aqueous HCl (1 mL) was heated at 60° C. for 4 days. The reaction mixture was neutralized with aqueous NaHCO3, extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure and the residue purified by HPLC to provide N-[2-(2-amino-6-methoxy-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide: MS m/z 520.0 (M+H)+.
Reaction SMILES: [ClH:1].O=[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]1[C:9]([O:11]C)=O.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>O>[ClH:1].[CH2:5]1[C:4]2[C:9](=[O:11])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:19][C:3]=2[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)C1C=NC=CC1=O
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1c2c(sc3ccccc13)CCNC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
2.33 g of methyl 4-oxo-3-pyridinecarboxylate hydrochloride and 1.1 ml of thiophenol were slowly added at 100° C. with stirring to 35 g of polyphosphoric acid and the mixture was stirred at 100° C. for 4 hours and was then poured into 500 ml of water. The pH of the mixture was adjusted to 8 by addition of sodium bicarbonate and the mixture was extracted with chloroform three times. The organic phase was washed with water, dried over magnesium sulfate and filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in a small amount of chloroform and the solution was acidified with a solution of hydrogen chloride in ether. Additional ether was added and the mixture was filtered. The product was crystallized from aqueous methanol and dried over P2O5 to obtain 1.365 g (54% yield) of 1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride melting at 270°-272° C. (decomp.)
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:22])[NH:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH3:18])=[C:9]([N+:19]([O-])=O)[CH:8]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:19][C:9]1[CH:8]=[C:7]([C:6]2[CH2:5][NH:4][C:3](=[O:22])[C:2]=2[CH3:1])[CH:12]=[CH:11][C:10]=1[N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH3:18]
Reactant: CC1=C(c2ccc(-n3ccnc3C)c([N+](=O)[O-])c2)CNC1=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1=C(c2ccc(-n3ccnc3C)c(N)c2)CNC1=O

Procedure:
1,5-Dihydro-3-methyl-4-[4-(2-methyl-1H-imidazol-1-yl)-3-nitrophenyl]-2H-pyrrol-2-one (7.3 g, 24 mmol) and tin (II) chloride dihydrate (28 g, 125 mmol) are combined in ethanol (330 mL), and the mixture is heated at reflux under a nitrogen atmosphere for 30 minutes. The mixture is cooled, made basic with saturated aqueous sodium bicarbonate, and filtered through celite. The filter cake is washed with ethanol, and the filtrates are evaporated. Chromatography of the residue on alumina provides the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:22]C(=O)C)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([OH:22])[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(O)c2)=C(C)C1=O
Yield: 61.2 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (22 mg, 0.059 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (12 mg, 0.0361 mmol, 61%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C=O)C>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:24]=[C:23]([Si:20]([CH3:22])([CH3:21])[CH3:19])[N:3]=[N:2]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Temperature: 95 °C
Yield: 99.9 %

Procedure:
A solution of (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 11.60 g, 32.0 mmol) in anhydrous DMF (50 mL) was treated with trimethylsilylacetylene (4.70 g, 6.77 mL, 48.0 mmol, 1.5 equiv) at room temperature, and the resulting reaction mixture was warmed up to 90-100° C. for 20 h. When TLC and HPLC/MS showed that the cycloaddition reaction was complete, the reaction mixture was cooled down to room temperature before being concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5R)-3-(3-fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one (1024, 14.72 g, 14.72 g theoretical, 100%) as brown oil, which was directly used in the subsequent reaction without further purification. For 1024: 1H NMR (300 MHz, DMSO-d6) δ 0.01 (s, 9H, SiCH3), 3.67 (dd, 1H, J=6.4, 9.2 Hz), 4.01 (t, 1H, J=5.4 Hz), 4.59 (d, 2H, J=4.9 Hz), 4.91-4.94 (m, 1H), 6.88 (dd, 1H, J=2.4, 8.7 Hz), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.58 (dd, 1H, J=7.5, 8.7 Hz), 7.73 (s, 1H, triazole-H); C15H18FIN4O2Si, LCMS (EI) m/e 461 (M++H).
Reaction SMILES: [CH2:1]([C@H:7]1[CH2:11][CH:10]([CH3:12])[O:9][C:8]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-:14].[Na+:15]>C(O)C>[OH:9][CH:10]([CH3:12])[CH2:11][C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([O-:13])=[O:14].[Na+:15]
Reactant: CCCCCC[C@H]1CC(C)OC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC[C@@H](CC(C)O)C(=O)[O-]
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To an ethanol solution of the compound prepared in Example 1(6) was added an equivalent of an aqueous solution of sodium hydroxide, and the mixture was stirred at 75° C. for 3 hours. The reaction mixture was concentrated to give the compound of the present invention having the following physical data.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1ccncc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2ccncc2Cl)CC1
Yield: 22.1 %

Procedure:
General procedure C was followed using isonipecotamide (43 mg, 0.34 mmol), 3,4,dichloropyridine (50 mg, 0.34 mmol), triethylamine (0.14 mL, 1.0 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a colourless oil (18 mg, 22%), m.p. 210-212° C.; umax (CHCl3)/cm−1 2360, 2342, 1653, 1581 1382, 1223, 1135, 1041; m/z (ESI) C11H15ClN3O requires 240.0898, found [M+H]+ 240.0899.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1nc2cccc3c2n1CCC3
Reactant: c1ccc(N2CCNCC2)cc1
Product: c1ccc(N2CCN(c3nc4cccc5c4n3CCC5)CC2)cc1
Yield: 45 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g) in 1-phenylpiperazine (10 ml) was stirred at 100° C., under nitrogen, for five hrs. The reaction mixture was quenched with saturated sodium bicarbonate solution (200 ml) and extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel; 4:1 dichloromethane-ethyl acetate). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate to give 2.2 g (45%) of product, mp 168°-169° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[CH3:23][Mg+].[Br-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH:20]([OH:21])[CH3:23])[C:3]=1[OH:22]
Reactant: O=Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)c1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of crude 6-fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (86.4 mg, 271 μmol; Intermediate 96) in THF (3 mL) was treated with MeMgBr (774 μL of a 1.4 M solution in Toluene/THF, 4 eq) at rt and stirred for 30 min. After 30 min another 2 eq and after 45 min another 4 eq. of Grignard solution were added and stirring continued for 15 min. The reaction mixture was quenched with sat. NH4Cl, extracted with EtOAc (3×), the combined org. phases washed with brine, dried and the solvent removed in vacuo to give a yellow-brownish solid (95.6 mg). This material was purified by prep. HPLC (15-45% MeCN/50 mM NH4HCO3) to yield the title compound as an yellowish solid (31.8 mg, 11% over 3 steps). MS (ESI+) for C16H14FNO4S m/z 318 (M-OH)+, 358 (M+Na)+.
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([CH3:30])[C:14]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([OH:19])[C:15]([F:18])([F:17])[F:16]>CCCCCCC>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C@@H:13]([CH3:30])[C@:14]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([OH:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccc2ncccc2c1)C(F)(F)F
Solvent: CC(C)O
Solvent: CCCCCCC
Product: C[C@H](c1ccc(Cl)cc1Cl)[C@@](O)(c1ccc2ncccc2c1)C(F)(F)F

Procedure:
These materials were obtained by preparative HPLC (Column: Chiralpack AD; solvent: 1% isopropanol in heptane) from racemic 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-quinolin-6-yl-butan-2-ol (example 52).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[N:14][CH:15]=1)=[O:9].Br[CH2:40][CH:41]1[CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:36][C:33]([F:34])([F:35])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][N:19]([CH2:40][CH:41]3[CH2:43][CH2:42]3)[CH2:20][CH:21]=2)=[N:14][CH:15]=1)=[O:9]
Reactant: Cc1ccccc1-c1cc(C2=CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(C2=CCN(CC3CC3)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.3 %

Procedure:
A mixture of 60 mg (0.11 mmol) 4-o-tolyl-1′,2′,3′, 6′-tetrahydro-[2,4′]bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide (Example 42), 0.011 ml (0.11 mmol) (bromomethyl)cyclopropane and 19 mg (0.14 mmol) potassium carbonate in 1.5 ml acetonitrile was stirred at room temperature for 15 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography afforded 28 mg (42%) of the title compound as a light brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[O:23])[C:12]4[N:21]([CH3:22])[N:20]=[CH:19][C:13]=4[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1.O>Br.C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[O:23])[C:12]4[N:21]([CH3:22])[N:20]=[CH:19][C:13]=4[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccc3[nH]c4cnn(C)c4c(=O)c23)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cn1ncc2[nH]c3cccc(-c4ccc(O)cc4)c3c(=O)c21
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 8-(4-methoxyphenyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 38, step 3, 41 mg, 0.14 mmol) in a mixture of 48% hydrobromic acid (1 ml) and acetic acid (1 ml) was refluxed for 7 h. After cooling to room temperature, water was added to the mixture. The formed solid was collected by filtration to give 37 mg (94%) of the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[C:26]([F:31])([CH3:30])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[C:26]([F:31])([CH3:30])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CC(F)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CN1C(=O)C(NC(=O)C(C)(F)C(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=482.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-fluoro-2-methyl-malonamic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10.1 g Pyridin-4-ol and 10 g 1-Fluoro-4-nitro-benzene and 46.1 g Cs2CO3 in 30 mL DMF was stirred at RT for 2 h. This solution was poured on to 300 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 11.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)=[O:12].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:25][CH:27]2[CH2:28][O:29]2)[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)=[O:12]
Reactant: ClCC1CO1
Reactant: Cc1sc(C(=O)CCc2ccc(O)cc2Cl)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1sc(C(=O)CCc2ccc(OCC3CO3)cc2Cl)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 18 h
Yield: 48 %

Procedure:
A solution of 3-(2-chloro-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (400 mg, 1.11 mmol, Intermediate 18) in isopropanol (10 mL) and 3 N aq. NaOH (6 mL) is treated with epichlorohydrine (554 mg, 4.43 mmol). The dark red reaction mixture is stirred at rt for 6 h before another portion of epichlorohydrine (554 mg, 4.43 mmol) is added. Stirring is continued for 18 h. The mixture is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-(2-chloro-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (222 mg) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=417.20.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[OH-].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 30 g of 2-(4-chlorophenoxymethyl)-2-tert.-butyloxirane, 9.8 g of 1,2,4-triazole and 1.2 g of solid potassium hydroxide in 70 ml of toluene and 7.5 ml of dimethyl sulphoxide was heated under reflux for 6 hours. After cooling to room temperature, 2 g of silica gel were added to the reaction mixture and it was then filtered. 75 ml of semi-concentrated hydrochloric acid were added to the filtrate, and the crystals which separated out thereby were filtered off with suction. Then 80 ml of water and aqueous sodium hydroxide solution were added to the crystalline solid so that the pH of the mixture was 13. It was stirred a further 2 hours at room temperature, then filtered off with suction and washed with water to neutrality. In this manner, 20 g (52% of theory) of 2-(4-chlorophenoxymethyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 84°-87° C. were obtained.