Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:16]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:16][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CCOCC
Product: ClCc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
40.0 g (0.33 mol) of thionyl chloride are added dropwise at room temperature to a suspension of 12.0 g (0.028 mol) of 3,4,5-trisbenzyloxybenzyl alcohol in 100 ml of diethyl ether. Heating is then carried out at reflux for 2 hours, resulting in a clear solution. After removal of excess thionyl chloride and solvent, the residue is recrystallised from isopropanol/hexane.
Reaction SMILES: [C:1]1([S:7]([C:10]#[C:11][CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>CO>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:11]([CH3:12])=[CH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: CC#CS(=O)(=O)c1ccccc1
Solvent: CO
Product: COc1ccc(NC(C)=CS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A stirred solution of 1-phenylsulphonylpropyne (0.25 g) in anhydrous methanol (10 ml) was treated with 4-anisidine (0.17 g) and the homogeneous mixture was allowed to stand at room temperature overnight. The methanol was removed in vacuo to give 1-(4-methoxyphenylamino)-1-methyl-2-(phenylsulphonyl)ethene (0.4 g) in the form of a dark brown oil [NMR (in deuterated dimethylsulphoxide: 2.16, 3.76, 7.04, 7.62, 7.84, 8.68 ppm].
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2]([N:1]=[C:34]4[CH2:37][CH2:36][CH2:35]4)[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Reactant: O=C1CCC1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1N=C1CCC1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
The product of Example 304F (0.285 g, 0.62 mmol) in N,N-dimethylacetamide (1.5 mL) was reacted with cyclobutanone (0.85 mL, 10.9 mmol) in a sealed tube in a microwave reactor at 130° C. for 45 minutes. The reaction was cooled to 25° C., concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. and the resulting residue was triturated with diethyl ether to give the title compound (0.178 g, 56%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)[CH:18]=[CH:19][CH:20]=1.[NH2:36][CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1>C(Cl)Cl>[S:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[CH2:37][NH:36][C:27]([C:26]1[C:25]([CH2:24][CH2:23][CH2:22][S:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:35])[F:34])[CH:16]=2)=[N:33][CH:32]=[CH:31][CH:30]=1)=[O:29]
Reactant: NCc1cccs1
Reactant: O=C(O)c1cccnc1CCCSc1cccc(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCc1cccs1)c1cccnc1CCCSc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
91 mg (0.6 mmol) of CDI were added to a solution of 240 mg (0.7 mmol) of 2-(3-(3-(trifluoromethyl)phenylthio)propyl)nicotinic acid (VB004) in DCM (7 ml), and stirring was carried out for 30 min at RT. 79 mg (0.7 mmol) of 2-(aminomethyl)thiophene were then added and stirring was carried out for a further 5 d at RT. The mixture was then washed with a 4M aq. NH4Cl sol. (2×10 ml) and a 1M NaHCO3 sol. (2×10 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA), yielding 134 mg (0.3 mmol, 44%). MS: m/z 437.1 [m+H]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[C:20]1([C:26]2[C:30]3[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=3[O:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na+].[I-]>CN(C=O)C>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:35][C:33]2[CH:32]=[CH:31][C:30]3[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][O:28][C:29]=3[CH:34]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1ccc2c(-c3ccccc3)coc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc3c(-c4ccccc4)coc3c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Step A (0.071 mmol, 1 eq) in 0.7 ml of DMF in a 16×100 mm tube treated with 3-phenyl-6-hydroxybenzofurane (0.078 mmol, 1.1 eq) Cesium Carbonate (0.213 mmol 3 eq) and NaI (0.071 mmol, 1 eq) and stirred at room temperature overnight. The reactants were filtered and washed with DMF several times. The solvent was evaporated under vacuo and the residue reconstituted in a mixture of Ethanol (2 ml) and NaOH (1M) (1 ml) and stirred at room temperature until reaction is completed by HPLC-MS. Then HCl (1M) was added (until pH=3) and the solvent were eliminated under vacuo. The residue was reconstituted in CH2Cl2/H2O and filtered through a hidrofobic syringer. The organic layer was separated, concentrated and purified by HPLC-MS to get the title compound. MS(ES) for C27H22O5 [M+H]+: 427.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@H:33]([CH2:36][CH3:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=1)=[O:22])[CH2:36][CH3:37]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: CC[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.22 mmol), (R)-2-aminobutan-1-ol (65 mg, 0.73 mmol), HBTU (108 mg, 0.28 mmol), and HOBT (44 mg, 0.28 mmol). Then added DMF (1 mL) followed by N,N-diisopropylethylamine (0.11 mL, 0.66 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-50% EtOAc) to afford 70 mg (61%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-hydroxymethyl-propyl)-amide as an off-white solid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[C:10]([CH3:26])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])[CH3:11]>C(O)(=O)C>[CH3:26][C:10]([C@H:6]1[C@@H:5]([CH2:4][CH:3]=[O:2])[NH:8][C:7]1=[O:9])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])[CH3:11]
Reactant: COC(C[C@H]1NC(=O)[C@H]1C(C)(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1)OC
Solvent: CC(=O)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC=O
Yield: 97.2 %

Procedure:
A solution of (3R,4R)-4-(2,2-dimethoxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-azetidin-2-one (64 mg) in 80% aqueous acetic acid (3.0 ml) was heated at 50°-55° C. for 4 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (20 ml) and the solution was washed with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (10 ml). The organic layers were combined, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give (3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)-azetidin-2-one (55 mg) as a solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][CH:6]([F:22])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:17]=[C:18]([F:21])[CH2:19][OH:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:20][CH2:19][C:18]([F:21])=[CH:17][C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH:6]([F:5])[F:22])=[CH:13][CH:12]=2)[CH2:16][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Yield: 99 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.92 ml), 1-(4-difluoromethoxyphenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl)cyclopropane Example 16) (0.49 g), benzene (24 ml) and pyridine (0.2 ml) to yield the title compound (0.55 g, 99%).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:4].S(Cl)([Cl:23])(=O)=O.N>ClCCl>[CH3:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([Cl:23])=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:4]
Reactant: CCC(=O)Nc1sccc1C(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)Cl
Agent: N
Solvent: ClCCl
Product: CCC(=O)Nc1sc(Cl)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.50 g of 2-(N-methylacetylamino)-3-(o-fluorobenzoyl)thiophene in 50 ml of dichloromethane is added dropwise 2.16 g of sulfuryl chloride in 30 ml of dichloromethane. After stirring the reaction mixture for overnight at room temperature, the reaction mixture is neutralized with aqueous ammonia, then extracted with methylene chloride. The methylene chloride extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to a residue. The residue is chromatographed on silica gel using chloroform as an eluent to give 2-(N-methylacetylamino)-3-(o-fluorobenzoyl)-5-chlorothiophene as an oil.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=1)#N.OS(O)(=O)=O.[OH2:17].[OH2:18]>C(O)(=O)C>[O:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3]([C:1]([OH:18])=[O:17])=[CH:4]1
Reactant: N#Cc1coc2ccccc12
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)c1coc2ccccc12

Procedure:
To a solution of benzofuran (75 g) in chloroform (600 ml) was added dropwise a solution of bromine (41 ml) in chloroform (150 ml) at -10° C. The temperature was slowly allowed to reach room temperature and chloroform was evaporated in vacuo, leaving the crude 2,3-dibromo-2,3-dihydrobenzofuran as a crystalline product which was used without further purification. Yield: 171 g. To the dibromoderivative (147 g) in ethanol (600 ml) was added a solution of KOH (59 g) in ethanol (200 ml). The mixture was refluxed for 2.5 hours. After cooling to room temperature the mixture was poured onto water and extracted with ethyl acetate (2×300 ml). The combined organic phases were worked-up and the 3-bromobenzofuran was subsequently purified by elution through silica gel using n-heptane as the eluent. Yield 51 g of a semicrystalline product. A solution of all of the thus obtained 3-bromobenzofuran and CuCN (33 g) in N-methyl-2-pyrrolidinone (350 ml) was heated at 190° C. under N2. With 1 hour intervals was added further CuCN (3×4.5 g). The mixture was poured into a solution of FeCl3.6H2O in water (610 ml) and concentrated hydrochloric acid (156 ml) while still hot. The resulting mixture was stirred at 60° C. for 1 hour and subsequently poured onto ice/water (5 l). Extraction with diethyl ether (3×300 ml) and working-up of the combined organic phases afforded crude, crystalline 3-cyanobenzofuran melting at 76°-82° C. Yield : 34 g. The 3-cyanobenzofuran was dissolved in a mixture of acetic acid:conc. H2SO4 :water 1:1:1 (660 ml) and refluxed for 3 hours. After cooling water was added and the 3-benzofurancarboxylic acid was finally extracted with diethyl ether (3×200 ml) and worked-up. Yield 37 g. Mp: 152°-156° C.
Reaction SMILES: CN(C)C=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1)[C:5](OCC)=[O:6].[CH3:23][C:24]([NH:34][NH:35][C:36](OC(C)(C)C)=O)([CH3:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1>C(O)(=O)C.C(OCC)C>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([C:4]2[CH:36]=[N:35][N:34]([C:24]([CH3:23])([CH3:33])[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:5]=2[OH:6])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1ccc(C(=CN(C)C)C(=O)OCC)cc1
Reactant: Cc1ccc(CC(C)(C)NNC(=O)OC(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCc1ccc(-c2cnn(C(C)(C)Cc3ccc(C)cc3)c2O)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Ethyl 3-(dimethylamino)-2-(4-hexylphenyl)acrylate and 0.50 g (1.8 mmol) of tert-butyl 2-(2-methyl-1-(p-tolyl)propan-2-yl)hydrazinecarboxylate were dissolved in 2 mL of acetic acid and stirred at 90° C. for 24 hours. After the stirring, the reaction mixture was mixed with 0.5 mL of acetic acid and stirred for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with distilled water, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=0:100 to 35:65). The resulting solid was washed with isopropyl ether to give 164 mg of the desired product as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH:13]1([S:19][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: SC1CCCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(SC2CCCCC2)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Ethyl 3-iodobenzoate (5.00 g) was dissolve din dioxane (100 mL), and cyclohexanethiol (2.32 mL), N,N-diisopropylethylamine (6.29 mL), Xantphos (2.09 g) and Pd2(dba)3 (1.66 g) were added thereto in that order, and stirred in a nitrogen atmosphere at 100° C. for 7 hours. After left cooled, ethyl acetate was added to it, then washed with water ad saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, the solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 25%, gradient) to give the intended compound (5.11 g) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Li][CH3:10].[NH4+].[Cl-].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH3:10])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(Br)cs1
Yield: 98.5 %

Procedure:
A solution of 4-bromo-2-thiophenecarboxaldehyde (Aldrich, 1.20 g, 6.28 mmol) in 15 ml of anhydrous ethyl ether is brought to −70° C. in a flask fitted with a thermometer, under an atmosphere of argon and with magnetic stirring. Then a 1.6 M solution of MeLi in ether (4.12 ml, 6.59 mmol) is added drop by drop between −70° C. and −60° C. The reaction is followed by CCM (eluent ether:petroleum ether=20:80). The mixture is hydrolysed in the cold with 5 ml of saturated NH4Cl solution, 20 ml of distilled water is added and the mixture is extracted with ether (3×40 ml). The ether phase is dried over MgSO4, filtered and evaporated to obtain 1.28 g of a slightly yellowish oil, 4-bromo-2-(1′-hydroxyethyl)thiophene (gross yield=98.5%).
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[C:14]1[C:23]2[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[C:5]12[CH:8]=[CH:9][CH:10]=[CH:11][CH:4]1[C:3]([NH:2][C:6]2=[O:7])=[O:12]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: FC(F)(F)c1cccc2c(Br)ccnc12
Product: O=C1NC(=O)C2(c3ccnc4c(C(F)(F)F)cccc34)C=CC=CC12

Procedure:
N-hydroxy-phthalimide and 4-bromo-8-trifluoromethylquinoline (a known compound) were reacted to obtain 0-(8-trifluoromethyl-4-quinolyl)-phthalimide which was reacted to obtain 0-(8-trifluoromethyl-4-quinolyl)-hydroxylamine melting at 152° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:22]Br.CO>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([Br:22])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ncccc1C(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1C(=O)c1cccnc1
Reaction time: 2 h

Procedure:
(2-Amino-pyridin-3-yl)-pyridin-3-yl-methanone (0.13 g, 0.65 mmol) is dissolved in glacial acetic acid (6 ml). Na2CO3 (0.075 g, 0.72 mmol) is added. After evolution of gas has finished, a solution of bromine (0.025 ml, 0.49 mmol) in acetic acid (3 ml) is added dropwise. Na2CO3 (0.075 g, 0.72 mmol) is added, followed by a second solution of bromine (0.025 ml, 0.49 mmol) in acetic acid (3 ml). The resulting yellow suspension is left to stir for 2 hour. The reaction is quenched by pouring onto ice water (150 ml), and neutralised using NaHCO3. The product is extracted with EtOAc and dried (MgSO4). Concentration in vacuo affords an oil, which is trituatuted with methanol to yield the title compound [M+H]+ 277.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][NH2:7])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[F:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH:2]1([CH2:5][O:6][NH:7][S:26]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[C:23]([F:24])[C:18]=2[F:17])(=[O:28])=[O:27])[CH2:4][CH2:3]1
Reactant: NOCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NOCC1CC1)c1ccc(F)c(F)c1F
Reaction time: 0.2 h
Yield: 67.9 %

Procedure:
To a stirring suspension comprised of O-cyclopropylmethyl-hydroxylamine hydrochloride (5.40 g, 0.0437 mol) in dichloromethane (20 ml) at ambient temperature under a nitrogen atmosphere was added diisopropylethylamine (10.8 ml, 0.062 mol). A solution comprised of 2,3,4-trifluorobenzenesulfonyl chloride (Oakwood Products, Inc., 1.00 g, 4.34×10−3 mol) in dichloromethane (120 ml) was added dropwise to the reaction vessel containing the stirring suspension over a 12 minute period. The reaction mixture was stirred for another 12 minutes and was quenched with 10% aqueous hydrochloric acid (140 ml). The biphasic mixture was stirred vigorously for 16 hours. The layers were separated and the organic phase was dried (MgSO4) and concentrated to 6 ml volume. The concentrated solution was administered to a flash silica column (Biotage, 90 g of silica gel). Elution with dichloromethane afforded 0.8283 g of a white amorphous solid; 68% yield; 1H-NMR (400 MHz; CDCl3 signal offset to δ 7.03; values reported are uncorrected) δ 7.50 (m,1H), 7.10 (s,1H), 6.95 (m,1H), 3.59 (d, 2H, J═7.2 Hz), 0.80 (m, 1H), 0.31 (m, 2H), 0.02 (m, 2H); 19F-NMR (376 MHz; CDCl3) δ−122.65 (m, 1F), −129.37 (m, 1F), −156.20 (m, 1F); MS (APCl−) 280 (M−1, 100), 210 (55), 195 (45).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A mixture of the 4-(pyridin-2-yloxymethyl)-benzaldehyde (26.8 g, 126 mmol) described in Manufacturing Example 2-2-2, nitromethane (34 mL, 630 mmol), ammonium acetate (19 g, 252 mmol) and acetic acid (90 mL) was stirred at 100° C. for 90 minutes. The reaction solution was partitioned into ethyl acetate and water. The organic layer was isolated, washed with water (5 times) and saturated aqueous sodium bicarbonate (once), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (31 g) as a crude product.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=O)[N:3]=1.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:32])[F:33])=[C:26]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:4]1[N:3]=[C:2]([CH3:1])[NH:6][N:5]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Product: Cc1nc(CC(=O)N2CCN(c3ccc(OC(F)F)c(OC4CCC4)c3)C[C@@H]2Cc2ccccc2)n[nH]1

Procedure:
Prepared by the method outlined for Example 189 using (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid and (S)3-benzyl-1-(3-cyclobutoxy-4-difluoromethoxy-phenyl)-piperazine (Example 4, Compound 92) as starting materials. Product as an oil. LC/MS (Method B) 2.66 min, [M+1]+ 512. Potency class A.