Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][CH3:29].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][N:15]([CH2:26][CH2:27][O:28][CH3:29])[CH2:14][CH2:13]1
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.31 g, 1.18 mmol), potassium carbonate (0.3 g, 2.17 mmol), acetonitrile (20 ml), 1-bromo-2-methoxy ethane (0.11 ml, 1.3 mmol). Yield: (0.29 g, 76%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 159-160° C. MS m/z (relative intensity, 70 eV) 321 (M+, 3), 277 (13), 276 (bp), 258 (24) 191 (9).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[Li+].[OH-]>C1COCC1.O>[C:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][C@@H:9]([O:10][CH3:11])[C@H:5]1[C:3]([OH:4])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@@H]1[C@H](OC)CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of (2S,3R)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (150 mg, 0.578 mmol) in THF (4 mL) and water (2.0 mL) was added LiOH (69.3 mg, 2.89 mmol) and the reaction mixture was stirred at RT for 40 h. Another aliquot of LiOH was added (69.3 mg, 2.89 mmol). Stirring was continued at RT for 60 h and subsequently at 50° C. for 16 h to complete the reaction. Water was added and volatiles were removed under reduced pressure. The aqueous phase was adjusted to pH 2 to 3 by addition of 1N aqueous HCl, followed by extraction with EtOAC (3×). The combined organics were dried (Phase separator) and concentrated in vacuo to give the title compound as a white solid. MS (LC/MS): 262 [M+Na]+, 190 [MH−tBu]+, 146 [MH−Boc]+, tR (HPLC conditions b): 3.51 min.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[BH4-].[Na+]>CO>[OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC/C=C\C/C=C\CCCCCCCC(O)CC(=O)OC
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
A cooled (0° C.) solution of (11Z,14Z)-methyl 3-oxoicosa-11,14-dienoate (2) (3.5 g, 10.4 mmol) in dry methanol (75 mL) was treated with NaBH4 (787 mg, 20.8 mmol) and stirred (20 min). The reaction mixture was quenched by the careful addition of HCl (5%, aq.) in an equal volume of ice and extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered, concentrated and the residue was subjected to flash chromatography (2%→10% EtOAc-hexanes) to yield (11Z,14Z)-methyl 3-hydroxyicosa-11,14-dienoate (3) (2.51 g, 71%) as a pale yellow oil. Rf 0.37 (30% EtOAc-hexanes). FW 338.51, C21H38O3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1CCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1CCc1ccccc1

Procedure:
A solution of (4-benzyloxy-2-phenethylphenoxy)acetic acid ethyl ester (1.77 mmol) in ethanol (15 mL) was treated with 5% Pd/C (70 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[C:7]([OH:20])[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[S:4]1(=[O:26])=[O:25])[CH3:2].[CH:27]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1.O>N1C=CC=CC=1>[CH:27]1([C:32]([O:20][C:7]2[C:6]3[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=3[S:4](=[O:26])(=[O:25])[N:3]([CH2:1][CH3:2])[C:8]=2[C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)C1CCCC1
Reactant: CCN1C(c2nnc(-c3ccccc3)o2)=C(O)c2ccccc2S1(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: O
Product: CCN1C(c2nnc(-c3ccccc3)o2)=C(OC(=O)C2CCCC2)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A mixture of 2-ethyl-4-hydroxy-3-(2-phenyl-1,3,4-oxadiazol-5-yl)-1,2-benzothiazine 1,1-dioxide (0.739 g), cyclopentanecarboxylic acid (0.34 g) and N,N'-dicyclohexylcarbodiimide (1.55 g) in pyridine (2.5 ml) was stirred at room temperature for 16 hours. Water (7 ml) was added to the reaction mixture and the solid thus formed was filtered and washed with water. The solid was then dissolved in chloroform and filtered. The filtrate was concentrated. The residue was recrystallized from toluene to give the title compound (0.776 g). M.P.: 194°-196° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:20]([Cl:21])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([F:22])[CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O.[Cl-].[Na+].O>[Cl:21][C:20]1[C:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[CH:13][C:14]([F:22])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(Cl)c(OC2CCC3(CC2)OCCO3)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(Oc2cc(F)c(C(=O)O)cc2Cl)CC1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To a solution of 4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoic acid (2.95 g, 8.92 mmol) in acetone (100 mL) was added 3 M hydrochloric acid (80 mL). The solution was heated to reflux for 17 hours and cooled to ambient temperature. The mixture was diluted with brine (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50% to afford the title compound as a colorless solid (1.14 g, 45%): 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=7.6 Hz, 1H), 6.77 (d, J=11.9 Hz, 1H), 4.82 (br s, 1H), 2.81-2.70 (m, 2H), 2.41-2.35 (m, 4H), 2.15-2.03 (m, 2H) (OH not observed); MS (ES−) m/z 285.1, 287.1 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1.O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:30]4[CH2:29][CH2:28][NH:27][CH:26]([CH3:25])[CH2:31]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CC1CNCCN1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(C)C4)c(F)cc3cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 30 cm3 of dimethyl sulphoxide and 5 g of 2-methylpiperazine is heated at a temperature close to 100° C., with stirring, for 2 hours. The solution obtained is poured, at this temperature, with stirring, into a mixture of 150 cm3 of water and 50 g of ice. 5 g of potassium carbonate are added at about 20° C. and the mixture is extracted with 3 times 50 cm3 of trichloromethane. The combined organic extracts are washed with twice 50 cm: of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue obtained is recrystallized from 30 cm3 of ethanol. 1.6 g of (RS)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[ b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 240° C.
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH2:31][C@H:32]([O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:33]=[CH2:34])[CH2:20][C:21]#[C:22][CH2:23][O:24]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:14]([Si:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:18][C@H:19]([CH2:31][C@H:32]([O:35][Si:36]([C:49]([CH3:50])([CH3:51])[CH3:52])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH:33]=[CH2:34])[CH2:20][C:21]#[C:22][CH2:23][OH:24])([CH3:15])([CH3:16])[CH3:17]
Reactant: C=C[C@H](C[C@H](CC#CCOC1CCCCO1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C=C[C@H](C[C@H](CC#CCO)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 86.1 %

Procedure:
25.16 g (34.4 mmol) of (5S,7S)-2-[5,7-bis-(tert-butyl-diphenylsilanyloxy)-non-8-en-2-ynyloxy]-tetrahydro-pyran was deprotected by treatment at ambient temperature with 1.30 g (15 mol %) of pyridinium p-toluenesulfonate in 290 ml of abs. MeOH. The solution gradually became homogeneous. After 18 h the reaction mixture was quenched by pouring onto crushed ice/Na2CO3, extracted with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=82/18) yielded 19.17 g of (5S,7S)-5,7-bis-(tert-butyldiphenyl-silanyloxy)-non-8-en-2-yn-1-ol as yellowish crystals of mp. 114-116°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccc(N)cc2)c1-c1ccccc1

Procedure:
5-Methyl-1-(4-nitrophenyl)-2-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester of Example 36 (4 mmol, 1.5 g) was dissolved in ethanol, and treated with 5% Pd/C (0.15 g). The mixture was hydrogenated with H2(g) at 45 psi. Upon completion of the reaction, the mixture was filtered through Celite, and the solvents removed under vacuum. Analysis of the resulting solid showed it was the named product (m.p. 181° C.-183° C.)
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])=[O:3].C(N(CC)CC)C.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[C:30]([F:31])([F:32])[F:33])[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CP(C)(=O)CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CP(C)(=O)CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
1-[(dimethylphosphoryl)methyl]piperazine (3.6 mmol) was dissolved in 20 mL of anhydrous dichloromethane. Triethylamine (4.04 g, 11 eq.) was carefully added. The reaction solution temperature rose to 30° C. before cooling down to room temperature after 5 minutes. After 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (60 weight %, 3.88 g, 7.9 mmol, 2.2 eq) was added in one portion, the reaction mixture was stirred at room temperature for 30 minutes under N2 protection. After the volatile components were evaporated, the reaction mixture was purified via column chromatography to give title compound as light yellow solid (740 mg). MS (LC/MS): 378.3 [M−]. 31P-NMR (300 MHz, CDCl3): 42.8.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:25])[CH:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH3:8].[CH3:26][N+:27]([O-:29])=[O:28].Cl>O.CS(C)=O>[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1([CH2:26][N+:27]([O-:29])=[O:28])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH3:8]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 3000-mL 4-necked round-bottom flask was placed potassium carbonate (93.2 g, 662 mmol, 0.50 equiv) and DMSO (2000 mL). The resulting solution was heated to 80° C. This was followed by the addition of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (368 g, 1.30 mol, 1.00 equiv, 95%) and CH3NO2 (417 g, 6.70 mol, 5.00 equiv, 98%) slowly. The resulting solution was stirred for 120 min at 90° C. After being cooled to room temperature, the reaction mixture was adjusted to ph 5 with HCl (0.5 mol/L) and diluted with 2000 mL of water. The resulting solution was extracted with 3×1500 mL of ether. The organic layers were combined, washed with 1×2000 mL of water and 1×2000 mL of saturated brine, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20˜1:15˜1:10) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[F:7][C:8]([F:36])([F:35])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:6])[C:30](=[O:32])[CH2:29][O:28][C:27]1[CH:26]=[CH:25][C:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:8]([F:7])([F:36])[F:35])=[N:10][N:11]=4)[N:14]=3)[CH2:19][CH2:20]2)=[CH:34][CH:33]=1
Reactant: O=C(O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CNCCOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN(C)C(=O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
N-(2-methoxyethyl)methylamine (25 mg, 0.28 mmol) was added to 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (100 mg, 0.24 mmol), HATU (108 mg, 0.28 mmol) and DIPEA (0.124 mL, 0.71 mmol) in DMF (2 mL). The resulting solution was stirred at ambient temperature for 3 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give N-(2-methoxyethyl)-N-methyl-2-[4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetamide (26 mg, 22%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzoic acid (16.0 g, 0.0864 mol) in dry DMF (100 mL) was added with stirring potassium carbonate (59.0 g, 0.43 mol) followed by methyl iodide (24.5 g, 0.173 mol) and the mixture was stirred for 3 h at ambient temperature. The reaction mixture was diluted with ice water (500 mL), extracted with EtOAc (3×100 mL) and the combined organic phases were washed with water (3×100 mL) and saturated brine solution (100 mL). The organic phase was dried (Na2SO4) and the solvent evaporated affording 17.0 g (99%) of 4-fluoro-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[C:5]([Cl:19])=[C:6]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:7][NH:8]C(=O)C(F)(F)F)([O-:3])=[O:2].[OH-].[Na+]>CO>[N+:1]([C:4]1[C:5]([Cl:19])=[C:6]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:7][NH2:8])([O-:3])=[O:2]
Reactant: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1Cl)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCc1ccc(Cl)c([N+](=O)[O-])c1Cl

Procedure:
A mixture of N-(3-nitro-2,4-dichloro-benzyl)-2,2,2-trifluoroacetamide (0.66 g, impure, content ˜50%), 4M NaOH-solution (1.3 mL, 5.2 mmol) and MeOH (15 mL) is refluxed for 4 h. Then the mixture is concentrated, diluted with water, acidified with 4M HCl, filtered, 4M NaOH-solution is added and it is extracted with EtOAc. The organic phase is dried with Na2SO4, filtered and concentrated. Yield 0.17 g
Reaction SMILES: N[C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(I)[I:19]>CC#N>[I:19][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: ICI
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1sc(I)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Ethyl 2-amino-4-phenyl-1,3-thiazole-5-carboxylate (6.1 g, 25 mmol), prepared according to known procedure (Yamaguchi K. et al. Biorg. Med. Chem. Lett. 1999, 9(7), 957-960), was dissolved in MeCN (240 ml) and treated with CH2I2 (7 ml, 150 mmol) isoamylnitrite (12 ml, 112.5 mmol). The reaction was stirred at room temperature for 1 hour. The solvents were removed under high vacuum and the mixture was submitted to flash chromatography by eluting with light petroleum/ethyl acetate (9:1) to give the title compound as a solid. Yield: 57%.
Reaction SMILES: C([O:3][C:4](=O)[N:5]([C:14]1[CH:19]=[C:18]([C:20]2[O:21][CH:22]=[C:23]([CH2:25][CH3:26])[N:24]=2)[N:17]=[C:16]([NH2:27])[C:15]=1[N+:28]([O-])=O)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)C>C(O)(=O)C.[Zn]>[NH2:27][C:16]1[C:15]2[NH:28][C:4](=[O:3])[N:5]([CH2:6][C:7]3[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[C:14]=2[CH:19]=[C:18]([C:20]2[O:21][CH:22]=[C:23]([CH2:25][CH3:26])[N:24]=2)[N:17]=1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(CC)co2)nc(N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCc1coc(-c2cc3c([nH]c(=O)n3Cc3ccc(C)nc3)c(N)n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
[2-amino-6-(4-ethyl-oxazol-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (74 mg) was dissolved in acetic acid (2 ml) and zinc powder (113 mg, Aldrich, 99%) was added to the reaction. The mixture was left to stir at room temperature under nitrogen for 16 hours. The reaction mixture was filtered directly onto a cation exchange cartridge (Bakerbond SCX, sulphonic acid bonded-phase, 1 g). The SCX cartridge was washed with methanol (2×4 ml) to remove impurities, then the product released with ammonia in methanol (2 M, 4 ml). The desired fractions were combined and evaporated to an off-white solid that was triturated with isopropanol, filtered, and then washed with isopropanol, providing the title compound (32 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.42 Hz, 3 H) 2.40 (s, 3 H) 2.44-2.56 (m, 2 H) 5.04 (s, 2 H) 5.98 (s, 2 H) 7.19 (d, J=8.02 Hz, 1 H) 7.23 (s, 1 H) 7.54 (dd, J=8.02, 2.34 Hz, 1 H) 7.79 (s, 1 H) 8.45 (d, J=2.34 Hz, 1 H) 10.65 (s, 1 H), LCMS Rt=1.73 m/z 351 [MH]+
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>CO>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8]
Reactant: C=C1CC(=O)O1
Reactant: OCCNCCO
Solvent: CO
Product: CC(=O)CC(=O)N(CCO)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A solution of 52.53 g (0.50 mol) diethanolamine in 100 ml MeOH was added dropwise to a solution of 40.00 g (0.48) diketene in 100 ml MeOH at 0° C. After stirring for 1 hour at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was purified by means of column chromatography. 81.32 g of product was obtained as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13]([CH2:26][CH2:27][CH3:28])=[N:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[OH:29].[C:30]([O:35]C)(=[O:34])[C@@H:31]([CH3:33])O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13]([CH2:26][CH2:27][CH3:28])=[N:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[O:29][C@@H:31]([CH3:33])[C:30]([OH:35])=[O:34]
Reactant: COC(=O)[C@@H](C)O
Reactant: CCCc1nc(Oc2ccc(Cl)cc2)ccc1-c1nn(C)c2cc(Cl)c(O)cc12
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1-c1nn(C)c2cc(Cl)c(O[C@@H](C)C(=O)O)cc12

Procedure:
The phenol from Step 2 (0.43 g, 1.0 mmol) and methyl (R)-lactate (0.16 g, 1.5 mmol) were reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH:26][C:27]([O:29][CH:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[CH3:31])=[O:28])=[CH:16][CH:15]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[Li+].[OH-]>CO.O>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH:30]([O:29][C:27]([NH:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=2)=[CH:19][CH:18]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(-c2onc(C)c2NC(=O)OC(C)c2ccccc2Cl)cc1
Reaction time: 2 h

Procedure:
To (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester (0.105 g, 0.20 mmol) in methanol (20 mL) was added 1N aqueous LiOH (5 mL, 5 mmol), and the reaction was stirred for 2 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound.