Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH:17]([C:19]#[C:20][CH3:21])[CH3:18])[CH:6]=1)(=O)C.C(=O)([O-])O.[Na+]>CO.S(=O)(=O)(O)O>[NH2:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH:17]([C:19]#[C:20][CH3:21])[CH3:18])[CH:6]=1
Reactant: CC#CC(C)Oc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To the suspension of methyl 4-acetoamido-5-chloro-2-{(3-pentyn-2-yl)oxy}benzoate (78.3 g) in methanol (700 ml), concentrated sulfuric acid (78 ml) was dropwisely added at 0° C. The temperature of the reaction mixture was raised to room temperature. After the reaction mixture was stirred over night at room temperature, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution (5 l) gradually. Crystal thus precipitated was recovered by filtration, washed with water and dried to obtain 66.5 g of the title compound as colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH2:14][OH:15]>CC#N.O=[Mn]=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH:14]=[O:15]
Reactant: CCC(=O)NCc1ccc(Cl)c(CO)c1
Agent: O=[Mn]=O
Solvent: CC#N
Product: CCC(=O)NCc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
MnO2 (5.61 g, 65.7 mmol) was added to a sol. of N-(4-chloro-3-hydroxymethyl-benzyl)-propionamide (2.99 g, 13.1 mmol) in CH3CN (255 mL) at rt. The mixture was stirred for 3 h at rt, and MnO2 (2.24 g, 26.2 mmol) was added again. The mixture was stirred for 1 h at rt, and the mixture was filtered through celite. The filtrate was evaporated under reduced pressure, and the residue was dried under high vacuum to yield the crude title compound (2.74 g, 93%) that was used further without purification. LC-MS: tR=0.76 min; ES+: 267.27.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:9]([CH3:14])=[N:10][NH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:20]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:23]=[CH:22][CH:21]=1.O>COCCOCCOC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:12]([CH3:13])=[N:11][N:10]([C:28]3[N:27]=[C:26]([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][N:25]=4)[CH:31]=[CH:30][CH:29]=3)[C:9]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: Cc1n[nH]c(C)c1SCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1nn(-c2cccc(-c3ccccn3)n2)c(C)c1SCc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 42.6 %

Procedure:
To a solution of 4-(4-chloro-benzylsulfanyl)-3,5-dimethyl-1H-pyrazole (0.708 g, 2.80 mmol) in 2-methoxyethyl ether (7 mL) was added sodium hydride (0.123 g (60% dispersion), 3.08 mmol). After stirring for 5 minutes, 6-bromo-[2,2′]bipyridinyl (0.691 g, 2.94 mmol) was added, and the reaction mixture was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, and water (100 mL) was added. The suspension was extracted with ethyl acetate (50 mL×2), and the combined organic extracts washed with brine (100 mL). The organic phase was dried (magnesium sulfate), filtered, and concentrated to afford a tan solid. Flash chromatography over silica (methanol/methylene chloride) followed by recrystallization from aqueous methanol provided 0.485 g (43%) of the product as a white solid: 1H NMR (CDCl3) δ 8.70-8.68 (m, 1H), 8.34 (d, J=7.9 Hz, 1H), 8.29 (d, J=7.9 Hz, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.86 (dt, J=2.0, 7.9 Hz, 2H), 7.35-7.31 (m, 1H), 7.22 (d, J=8.3 Hz, 2H), 6.99 (d, J=8.3 Hz, 2H), 3.65 (s, 2H), 2.45 (s, 3H), 2.21 (s, 3H) ppm. 13C NMR (CDCl3) δ 155.7, 154.5, 153.8, 152.9, 149.5, 145.9, 139.7, 137.3, 137.2, 133.1, 130.7, 128.7, 124.2, 121.3, 118.5, 116.1, 110.0, 40.3, 13.6, 12.3 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11]Br.O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:11][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([F:1])=[CH:3][C:4]=1[OH:10]
Reactant: BrBr
Reactant: COc1ccc(O)cc1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(Br)c(O)cc1F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
3-Fluoro-4-methoxy-phenol (21.32 g; 0.15 mol) prepared according to literature [Freedman, J.; Stewart, K. T.; J. Heterocycl. Chem. 1989, 26, 1547-1554] is dissolved in dry dichloromethane (300 mL). The well stirred reaction mixture is cooled to −15° C. (ice/salt). A solution of bromine (23.97 g; 0.15 mol) in dry dichloromethane (75 mL) is dropped into the reaction mixture. After complete addition stirring is continued for one hour. Water (150 mL) containing sodium sulfite (3.0 g) is added to the reaction mixture. Stirring is continued at ambient temperature for 30 min. The organic layer is separated, washed with water (100 mL) and dried over MgSO4 in the presence of decolorizing charcoal. After filtration the solvent is completely removed under reduced pressure. The residue is crystallized from tert-butylmethylether/hexane to yield the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](Br)(Br)([Br:12])[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:11][C:10]([Br:12])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(C=C(Br)Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
4-Fluoro benzaldehyde (1.23 g, 0.00995 mol) was dissolved in DCM (120 mL). Carbon tetrabromide (6.6 g, 0.0199 mol) and triphenylphosphine (10.42 g, 0.0398 mol) were added. The mixture was stirred at RT for 3 h. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography (100% pentane in silica 100-200 mesh, Diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (1.1 g, 44% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cncc(Br)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.8 %

Procedure:
To a solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol) in pyridine (3.00 mL) was added benzenesulfonyl chloride (0.75 mL, 5.78 mmol) dropwise at 0° C. The mixture was stirred for 40 min at room temperature. The resulting solid was filtered, washed with water, and dried under vacuum to give N-(5-bromopyridin-3-yl)benzenesulfonamide (1.39 g, 77%) as a brown solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 7.58-7.68 (4H, m), 7.79-7.81 (2H, m), 8.27 (1H, d, J=2.4 Hz), 8.37 (1H, d, J=2.0 Hz), 10.91 (1H, brs).
Reaction SMILES: BrC1C(F)=CC2OCCN3C(C(O)C4C=CC=C(C(F)(F)F)C=4)=C(C(O)=O)N=C3C=2C=1.[Br:32][C:33]1[C:34]([F:59])=[CH:35][C:36]2[O:42][CH2:41][CH2:40][N:39]3[C:43]([CH:50]([OH:57])[C:51]4[S:55][CH:54]=[N:53][C:52]=4[CH3:56])=[C:44]([C:46]([O:48]C)=[O:47])[N:45]=[C:38]3[C:37]=2[CH:58]=1.[OH-].[Li+]>>[Br:32][C:33]1[C:34]([F:59])=[CH:35][C:36]2[O:42][CH2:41][CH2:40][N:39]3[C:43]([CH:50]([OH:57])[C:51]4[S:55][CH:54]=[N:53][C:52]=4[CH3:56])=[C:44]([C:46]([OH:48])=[O:47])[N:45]=[C:38]3[C:37]=2[CH:58]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1scnc1C)CCOc1cc(F)c(Br)cc1-2
Agent: O=C(O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Product: Cc1ncsc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-[hydroxy-(4-methylthiazol-5-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylic acid was prepared similarly according to the procedure for the synthesis of 10-bromo-9-fluoro-3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid. Methyl 10-bromo-9-fluoro-3-[hydroxy-(4-methylthiazol-5-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate was reacted with lithium hydroxide to the crude title compound which was carried forward without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:18][CH:19]=3)=[O:24])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CN(C)CCN1CCCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-amino-1-(2-dimethylaminoethyl)-1,2,3,4-tetrahydroquinoline (D14) (38 mg, 0.152 mmol) in DCM (1 ml) was added 4-biphenylcarboxylic acid (45 mg, 0.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol) and 4-dimethylaminopyridine (2.8 mg, 0.022 mmol) and the reaction stirred at ambient temperature overnight. The crude reaction mixture was loaded directly onto a silica SPE column and elution with EtOAc followed by 1% triethylamine/EtOAc gave the title compound as a red gum. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.75 (br, 1H), 7.70 (d, 2H), 7.64 (d, 2H), 7.47 (t, 2H), 7.39 (t, 1H), 7.01 (d, 1H), 6.92 (d, 1H), 6.82 (dd, 1H), 3.43 (m, 2H), 3.33 (m, 2H), 2.73 (t, 2H), 2.55 (m, 2H), 2.33 (s, 6H), 1.95 (m, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23](Cl)=[O:24])(C(C)(C)C)(C)C.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.FC(F)(F)C(O)=O>C1COCC1>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:24])[C:10]([CH2:9][OH:8])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)Cl
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCCCC1)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 50 mg (0.11 mmol) of chloroformate 6-1 in THF was added 45 μL (0.32 mmol) of triethylamine, and 32 μL (0.32 mmol) of piperidine. After stirring overnight at room temperature, ˜300 μL of trifluoroacetic acid was added and stirring was continued for 2 h. The mixture was partitioned between EtOAc and 10% KHSO4, the layers were separated, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 6-2 as a white solid. Data for 6-2: 1HNMR (500 MHz, d6-DMSO) δ 7.4-7.2 (m, 8H), 6.4 (s, 1H), 5.1 (m, 1H), 4.8 (m, 1H), 4.7 (m, 1H), 4.35 (m, 1H), 4.1 (m, 1H), 3.2-3.0 (m, 4H), 1.8-1.6 (m, 6H) ppm. HRMS (ES) calc'd M+H for C23H24F2N2O2: 399.1879. Found: 399.1860.
Reaction SMILES: COC([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16])=O.[C:17](#N)C.C[Si](I)(C)C>C(OCC)(=O)C>[NH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]([CH3:17])[C:7]1=[O:16]
Reactant: COC(=O)NC1C(=O)NCc2ccccc21
Reactant: CC#N
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Product: CN1Cc2ccccc2C(N)C1=O
Temperature: 65 °C

Procedure:
Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 ML of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80° C. for 3 hrs and then cooled and poured into a separatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 and then with 5% NaHSO3. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87%.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:18][CH:19]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Nc2ncc(F)c(Nc3ccccc3C(=O)NC(C)C)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2ccc(CO)cc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of ethyl 4-({5-fluoro-4-[(2-{[(1 methylethyl)amino]carbonyl}phenyl)amino]-2-pyrimidinyl}amino)benzoate (1.47 g, 3.36 mmol) in THF (80 mL) was slowly added a solution of LiAlH4 (1.0M solution, 3.0 eq) at 0° C. After the addition was complete, the reaction mixture was slowly warmed up to room temperature and stirred for 16 h. The reaction mixture was quenched with 15 mL of 1.0 M Rochelle's solution. The water phase was extracted by EtOAc (2×30 mL) and the combined organic phases were washed by brine (3×30 mL) then dried over Na2SO4. The solvent was evaporated to produce a solid, which was washed with hexane (3×30 mL), then dried in vacuo to give the desired product. (1.15, 87% yield). MS: M(C21H22FN5O2)=395.44, (M+H)+=396
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][C@H:20]1[CH2:22][O:21]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:21]1[CH2:22][C@H:20]1[CH2:19][O:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH:16]=[CH:15][CH:14]=1
Reactant: ClC[C@H]1CO1
Reactant: Oc1cccc(-c2cccc3cccnc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OC[C@@H]2CO2)cc(-c2cccc3cccnc23)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(quinolin-8-yl)phenol (221 mg, 1 mmol) and (R)-2-(chloromethyl)oxirane (114.6 mg, 1.2 mmol) in CH3CN (10 mL) had K2CO3 (690 mg, 5 mmol) added to it. The reaction mixture was then stirred at 80° C. for 4 h. The solid was removed by filtration, the filtrate concentrated, and the crude product used in the next step without further purification. ESI-MS (m/z): 278.3 [M+1]+.
Reaction SMILES: N1C=NC=N1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=O)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1.Cl.[OH:29][NH3+:30]>C(#N)C.C(O)C.O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[N:30][OH:29])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: [NH3+]O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: ON=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 42.8 %

Procedure:
269 g (1 mol) of ω-bromo-2,4-dichloroacetophenone were dissolved in 250 ml of acetonitrile. This solution was added dropwise to a suspension, boiling under reflux, of 69 g (1 mol) of 1,2,4-triazole and 150 g of potassium carbonate in 2 liters of acetonitrile. After heating the mixture under reflux for 20 hours, the cooled suspension was filtered, the filtrate was freed from solvent, the residue was taken up in ethyl acetate and the ethyl acetate solution was washed with water, dried over sodium sulphate and freed from solvent. The residue from the ethyl acetate crystallized out when isopropanol was added. After recrystallizing from ligroin/isopropanol, 154 g (60% of theory) of ω-(1,2,4-triazol-1-yl)-2,4-dichloroacetophenone of melting point 117° C. were obtained. ##STR7## 106.8 g (0.44 mol) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-one were dissolved in 780 ml of ethanol, 48 g of hydroxylammonium hydrochloride were added and the mixture was heated under reflux for 5 hours. Thereafter, 1,000 ml of water were added, and the reaction mixture was filtered. 51 g (45% of theory) of 1-(2,4-dichlorophenyl)-1-oximino-2-(1,2,4-triazol-1-yl)-ethane of melting point 165°-170° C. were obtained. ##STR8##
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:11][CH:12]=[C:13]([C:15](OCC)=[O:16])[N:14]=2)=[CH:6][CH:5]=1.[Li+].[BH4-].[OH-].[Na+]>CC1OCCC1.C1COCC1.CCOC(C)=O>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1csc(-c2ccc(OC(F)(F)F)cc2)n1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1csc(-c2ccc(OC(F)(F)F)cc2)n1
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a solution of ethyl 2-[4-(trifluoromethoxy)phenyl]-1,3-thiazole-4-carboxylate (71 mg, 0.224 mmol) in 2-MeTHF (1 mL) was added 2M LiBH4 (0.224 mL, 0.448 mmol) in THF slowly at RT. After 90 min the mixture was quenched by the addition of 2M NaOH (0.6 mL, 1.200 mmole). The mixture was stirred for 4 hr then diluted with EtOAc, filtered through a pad of Celite and concentrated to give the title compound (60 mg, 97%). 1H NMR (400 MHz, CDCl3): δ 8.00-7.96 (m, 2 H); 7.31-7.25 (m, 2 H); 7.21 (s, 1 H); 4.84 (d, J=5.6 Hz, 2 H); 2.29-2.22 (m, 1 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: Nc1ccccc1F
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3ccccc3F)c2c2ccccc12
Yield: 74.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-fluoroaniline (96 mg, 0.87 mmol) to provide 189 (98 mg, 74% yield) as a white solid. LC-MS (M+H=306, obsd.=306).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: Cc1nc2nc(Cl)ccc2n1Cc1ccccc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1nc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1Cc1ccccc1
Temperature: 110 °C

Procedure:
A reaction vessel was charged with 1-benzyl-5-chloro-2-methyl-1H-imidazo[4,5-b]pyridine (1.00 g, 3.88 mmol, from Step 2), di-tert-butyl hydrazine-1,2-dicarboxylate (1.0 g, 4.3 mmol, Aldrich), cesium carbonate (1.26 g, 3.88 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.305 g, 0.39 mmol, Aldrich) and toluene (20 mL). The mixture was degassed by bubbling a stream of nitrogen through the solution for 10-15 minutes. The vessel was then sealed and heated to 110° C. for 9 hours. Upon cooling to room temperature, the mixture was applied to silica gel for flash chromatography, and a first pass purification was performed by eluting with a gradient from 0-100% EtOAc in hexanes, followed by elution with a gradient from 0-10% MeOH/DCM. A second purification of the material thus isolated was performed eluting with 100% EtOAc. (0.97 g, 55%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH:11]2[OH:23])=[CH:5][CH:4]=1.[H][H]>[Pd].CO>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[OH:23])=[CH:5][CH:4]=1
Reactant: OC1CN(Cc2ccccc2)CCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: OC1CNCCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 100 %

Procedure:
A mixture of 27.8 parts of 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)-3-piperidinol hydrochloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 80 parts of acetonitrile. The product was filtered off and dried, yielding 21.9 parts (100%) of 4-[bis(4-fluorophenyl)methylene]-3-piperidinol hydrochloride;mp.>260° C. (intermediate 24).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:13]2[N:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:48][C:49]1[CH:54]=[CH:53][C:52]([S:55]([NH:58][CH2:59][C:60](O)=[O:61])(=[O:57])=[O:56])=[CH:51][CH:50]=1>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:13]2[N:18]=[CH:17][C:16]([CH2:19][NH:20][C:60](=[O:61])[CH2:59][NH:58][S:55]([C:52]3[CH:53]=[CH:54][C:49]([CH3:48])=[CH:50][CH:51]=3)(=[O:57])=[O:56])=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)NCC(=O)O)cc1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCC(=O)NCc2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a dichloromethane (6 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine hydrochloride (40 mg, 0.0898 mmol) obtained in Example 66 were added triethylamine (45 μl, 0.324 mmol), 4-dimethylaminopyridine (5 mg, 0.0449 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.108 mmol) and N-p-tosylglycine (25 mg, 0.108 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was then washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then, concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2.3 eluate was concentrated under reduced pressure to give the title compound (41 mg, 0.0661 mmol, 73%) as a white powder.