Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[C:27]([CH3:44])=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:43])([CH3:42])[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[C:27]([CH3:44])=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:43])[C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 58.7 %

Procedure:
1.40 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.636 g of isopropyl 2-(6-chloro-7-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 190-200° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (185:15:2). The desired fraction was collected to yield 0.737 g of isopropyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-7-methylimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 6 ml of ethanol; 3.15 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 7 hours. After cooling, the mixture was concentrated under reduced pressure; under ice cooling conditions, 1.89 ml of 1 N hydrochloric acid was added; the residue was washed with ethyl acetate. To the water layer, 1.89 ml of 1 N hydrochloric acid was added to saturate with sodium chloride, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure; 1.89 ml of 1 N hydrochloric acid was added to the residue, followed by concentration to dryness under reduced pressure. The residue was crystallized by the addition of ethyl ether, collected by filtration, washed with ethyl ether and dried to yield 0.445 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (1 g, 5.402 mmol) in MeOH was added H2SO4 (2.9 ml). The reaction mixture was refluxed overnight, and then cooled to room temperature and concentrated. The residue was diluted with EtOAc and washed with a saturated NaHCO3 solution. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography to afford the pure compound methyl 2-fluoro-4-nitrobenzoate (1.05 g, 98%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:14]1[N:19]=[C:18]2[N:20]([C@@H:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:23])[NH:22][C:17]2=[CH:16][CH:15]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:6][C:14]1[N:19]=[C:18]2[N:20]([C@@H:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:23])[NH:22][C:17]2=[CH:16][CH:15]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3[nH]c(=O)n([C@H](C)c4cccnc4)c3n2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1cccnc1)n1c(=O)[nH]c2ccc(N)nc21

Procedure:
A solution of (R)-tert-butyl 2,4-dimethoxybenzyl(2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)carbamate in methylene chloride (15 mL) was treated with TFA (15 mL) and triethylsilane (1.0 mL) for one hour. The mixture was concentrated to provide the intermediate (R)-5-amino-3-(1-(pyridin-3-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (68), which was dissolved in acetonitrile (50 mL) and stirred vigorously with di-tert-butyl dicarbonate (1.0 g) and potassium carbonate (3.0 g) for 2 h. Methylene chloride (200 mL) and water (100 mL) was added and the organic layer was separated. The aqueous layer was extracted with another 100 mL of methylene chloride. The combined organic layers were separated, dried over sodium sulfate, filtered, and concentrated. Column chromatography (2→3→4% MeOH in methylene chloride) provided 235 mg (R)-tert-Butyl 5-amino-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (69).
Reaction SMILES: [CH2:1]([N:4]([CH:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[O:33]1[CH2:3][CH:2]1[CH2:1][N:4]([CH:17]([CH3:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN(C(C)c1ccccc1)S(=O)(=O)c1ccc(CCC)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCc1ccc(S(=O)(=O)N(CC2CO2)C(C)c2ccccc2)cc1
Yield: 91 %

Procedure:
A solution of 3.27 g (0.01 mole) of N-allyl-N-α-methylbenzyl-4-propylbenzenesulfonamide in 30 ml of chloroform was admixed with 4.31 g (0.02 mole) of metachloroperbenzoic acid for reaction under reflux for 2 hours. Thereafter, an aqueous sodium sulfite solution was added to decompose the excess of the peroxide. After washing with an aqueous sodium bicarbonate solution and water, the chloroform solution was dried over anhydrous magnesium sulfate, concentrated and purified by the silica gel chromatography to obtain the intended product (Compound No. 14). The yield was 91% and the nD25.0 value was found to be 1.5445. The elemental analysis of the product was effected with the results shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[O:18]CC1C=CC=CC=1)[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7].[C:33]1(=O)[O:38][C:36](=[O:37])[CH:35]=[CH:34]1>C(O)(=O)C>[O:37]=[C:36]1[CH:35]=[CH:34][C:33](=[O:38])[N:1]1[C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[OH:18])[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N)c(OCc1ccccc1)c2=O
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N1C(=O)C=CC1=O)c(O)c2=O
Reaction time: 18 h
Yield: 26.9 %

Procedure:
To a solution of N-(2-aminobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0 050 g, 0.114 mmol) in acetic acid (1.5 mL) was added maleic anhydride (0.013 g, 0.131 mmol) and the reaction mixture stirred in a sealed tube at 115 C for 18 h. Acetic acid was evaporated in vacuo and the residue was purified by preparative HPLC (YMC-Pack C-18) to afford the title compound (0.013 g, 27% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 8.03 (1H, broad t), 7.59 (1H, m), 7.48 (2H, m), 7.19 (1H, m), 6.92 (2H, s), 4.48 (2H, d, J=6.1 Hz), 4.04 (4H, s), 1.62 (6H, s); HRMS calcd for C21H21N4O6: 425.1461. Found 425.1451.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14]C1C=CC=CC=1C(=O)C>CCOC(C)=O>[F:14][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10]
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1F
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccccc1F

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.0 g of 2′-fluoroacetophenone and 2.86 mL of EtOAc to yield Intermediate 20: 1H NMR (400 MHz, CDCl3, enol form) δ7.70 (dt, 1H. J=1.79, 7.69), 7.45 (m, 1H), 7.24 (m, 1H), 7.10 (m, 1H), 6.28 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[C:20]([O:24][C:25](=[O:26])[NH:27][CH2:28][C:29](=[O:30])[N:17]1[CH2:18][CH2:19][CH:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]2)[CH2:16]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: c1ccc(C2CCN(C3CCNC3)CC2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
To a mixture of 4-phenyl-1-pyrrolidin-3-yl-piperidine dihydrochloride (preparation #7) (3.0 g, 9.90 mmol), tert-butoxycarbonylamino-acetic acid (1.73 g, 9.90 mmol) and EDC (1.90, 9.90 mmol) in DCM (60 mL) was added Et3N (5.5 mL, 39.6 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. DCM was added and the organic layer was washed with water and saturated NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using 5% MeOH/EtOAc as the mobile phase to afford {2-oxo-2-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethyl}-carbamic acid tert-butyl ester (1.47 g, 38% yield). RP-HPLC (Table 1, Method b) Rt 1.54 min; m/z: (M+H)+ 388.
Reaction SMILES: N1(C2C=C(/C=C\C3C=C(C=CC=3)CO)C=CC=2)C=CC=C1.N1C=CC=C(C2C=C(/C=C\C3C=C(C=CC=3)CO)C=CC=2)C=1.[S:44]1[CH:48]=[CH:47][C:46]([C:49]2[CH:50]=[C:51](/[CH:55]=[CH:56]\[C:57]3[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=3)[CH2:60][OH:61])[CH:52]=[CH:53][CH:54]=2)=[CH:45]1.N1(C2C=C(CCC3C=C(C=CC=3)CO)C=CC=2)C=CC=C1.N1C=CC=C(C2C=C(CCC3C=C(C=CC=3)CO)C=CC=2)C=1>>[S:44]1[CH:48]=[CH:47][C:46]([C:49]2[CH:50]=[C:51]([CH2:55][CH2:56][C:57]3[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=3)[CH2:60][OH:61])[CH:52]=[CH:53][CH:54]=2)=[CH:45]1
Reactant: OCc1cccc(/C=C\c2cccc(-c3ccsc3)c2)c1
Agent: OCc1cccc(/C=C\c2cccc(-c3cccnc3)c2)c1
Agent: OCc1cccc(/C=C\c2cccc(-n3cccc3)c2)c1
Agent: OCc1cccc(CCc2cccc(-c3cccnc3)c2)c1
Product: OCc1cccc(CCc2cccc(-c3ccsc3)c2)c1

Procedure:
When the same reduction as in Referential Example 47 is carried out using (Z)-3-[2-[3-(1-pyrrolyl)phenyl]ethenyl]benzyl alcohol or (Z)-3-[2-[3-(3-pyridyl)phenyl]ethenyl]benzyl alcohol instead of the starting (Z)-3-[2-[3-(3-thienyl)phenyl]ethenyl]benzyl alcohol, 3-[2-[3-(1-pyrrolyl)phenyl]ethyl]benzyl alcohol and 3-[2-[3-(3-pyridyl)phenyl]ethyl]benzyl alcohol are obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])[CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])[CH:16]=1)[CH2:12][NH:25][CH:22]1[CH2:24][CH2:23]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: COC/C=C/c1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: COC/C=C/c1cc(CNC2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(1E)-3-methoxyprop-1-en-1-yl]benzaldehyde (1 eq.) from the previous step in DCM was added cyclopropanamine (2 eq.) and magnesium sulfate (1.5 eq.). The resulting suspension was stirred at rt for 12 h. The insolubles were removed via filtration. Concentration of the filtrate in vacuo afforded the crude imine as a yellow oil. This was then taken up in methanol (0.3 M), and then sodium borohydride (1.5 eq.) was added portionwise at 0° C. over 5 min. The reaction mixture was slowly warmed to rt over 1 h and then stirred at it for 2 h. The reaction was slowly quenched with saturated aqueous NaHCO3 solution, and the resulting mixture was extracted with ether. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as a golden, yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C1N2CN3CN(C2)CN1C3.[C:27](=O)(O)[O-:28].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([CH:27]=[O:28])=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C([O-])O
Reactant: CCOC(=O)COc1cc(Cl)ccc1OC
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1cc(Cl)c(C=O)cc1OC
Temperature: 60 °C
Reaction time: 9 h

Procedure:
To a stirred solution of ethyl 2-(5-chloro-2-methoxy-phenoxy)acetate (606 mg) in trifluoroacetic acid (12 ml) was added hexamethylenetetramine (382 mg) at room temperature, and the mixture was stirred for 9 hours at 60° C. After concentration of the reaction mixture under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to the residue, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=6/1) gave ethyl 2-(5-chloro-4-formyl-2-methoxyphenoxy)acetate (354 mg).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][NH:12][N:11]=2)=[CH:6][CH:5]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1>C(OCC)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:12]2[CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:21])=[CH:9][CH:8]=3)=[N:11]2)=[S:31])=[CH:25][CH:24]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: FC(F)Oc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: CCOCC
Product: FC(F)Oc1ccc(C2=NN(C(=S)Nc3ccc(Cl)cc3)CC2c2ccccc2)cc1

Procedure:
A mixture of 5.8 g. of 3-(4-difluoromethoxyphenyl)-4-phenyl-2-pyrazoline and 3.4 g. of 4-chlorophenylisothiocyanate in 200 ml. of anhydrous ethyl ether was refluxed for 6 hours to react them. After cooling the reaction mixture, the precipitated crystal (6.1 g.) was separated by a filtration. It was confirmed that the product was 1-(4-chlorophenylthiocarbamoyl)-3-(4-difluoromethoxyphenyl)-4-phenyl-2-pyrazoline (melting point of 158.0°-161.0° C.) by the NMR spectrum.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:20][C:21]1[O:25][C:24]([CH:26]([C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)[NH2:27])=[N:23][N:22]=1>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:27][CH:26]([C:24]3[O:25][C:21]([CH3:20])=[N:22][N:23]=3)[C:28]3([CH3:32])[CH2:31][O:30][CH2:29]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnc(C(N)C2(C)COC2)o1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: Cc1nnc(C(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)C2(C)COC2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and (5-methyl-1,3,4-oxadiazol-2-yl)-(3-methyloxetan-3-yl)methanamine (example 245b) as starting materials and isolated (31 mg, 44%); MS (ESI, m/z): 441.7 (M+H+).
Reaction SMILES: C(C1C=CC(C2C=C(C(F)(F)F)SC=2CO)=CC=1)C.OC1C=CC(CCC(OCC)=O)=C(F)C=1F.[CH2:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[S:46][C:45]=2[CH2:53][O:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH2:62][C:63]([O:65]CC)=[O:64])=[C:57]([F:68])[C:56]=2[F:69])=[CH:40][CH:39]=1)[CH3:37]>>[CH2:36]([C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:48]=[C:47]([C:49]([F:52])([F:50])[F:51])[S:46][C:45]=2[CH2:53][O:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH2:62][C:63]([OH:65])=[O:64])=[C:57]([F:68])[C:56]=2[F:69])=[CH:42][CH:43]=1)[CH3:37]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(C(F)(F)F)cc2-c2ccc(CC)cc2)c(F)c1F
Agent: CCOC(=O)CCc1ccc(O)c(F)c1F
Agent: CCc1ccc(-c2cc(C(F)(F)F)sc2CO)cc1
Product: CCc1ccc(-c2cc(C(F)(F)F)sc2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 207 by coupling of (3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methanol and ethyl 3-(4-hydroxy-2,3-difluoro phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[S:14])[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19]O>[OH-].[Na+].CI>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:19])[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: S=c1[nH]c(-c2ccc(I)cc2)cc2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nc(-c2ccc(I)cc2)cc2ccnn12
Yield: 62 %

Procedure:
To a solution of 5-(4-iodo-phenyl)-6H-pyrazolo[1,5-c]pyrimidine-7-thione (compound E1)(2.09 g) in 2M aqueous NaOH (3 ml) and methanol (40 ml), methyl iodide (0.376 ml) is added at ambient temperature. After 30 min at this temperature further methyl iodide (0.376 ml) is added. After 60 min the mixture is neutralized with 2M hydrochloric acid and evaporated. The residue is partitioned between dichloromethane and water and the organic phase is washed twice with water. The organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A nearly colorless solid (1.35 g, 62%) is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=3)[C:7](=[CH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:22])[C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl.C(N=C=NCCCN(C)C)C.O[C:45]1[C:53]2[N:52]=N[NH:50][C:49]=2[CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=3)[C:7](=[CH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:50][C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:53]=3[NH2:52])=[O:31])=[O:22])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCCNC(=O)C=C1c2cc([N+](=O)[O-])ccc2-c2ccc([N+](=O)[O-])cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)C=C1c2cc([N+](=O)[O-])ccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
6-(2-(2,7-dinitro-9H-fluoren-9-ylidene)acetamido)hexanoic acid (425 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (433 mg, 84% yield) as a brown solid. LC-MS (m/z) 516 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH2:5].CC(C)([O-])C.[K+].[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][OH:22])=[CH:18][CH:17]=1)[CH3:14]>CN(C)C=O>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][O:22][CH2:3][CH2:4][NH2:5])=[CH:18][CH:17]=1)[CH3:12]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: NCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(COCCN)o1

Procedure:
A solution of 2-chloroethylamine hydrochloride (6.25 g) in dry dimethylformamide was added dropwise to a stirred, cooled solution of potassium tert-butoxide (8.96 g) and 5-(dimethylamino)methyl-2-furanmethanol (12.4 g) in the same solvent. After 2 hr solvent was removed, the residue basified and extracted with ethyl acetate. The residue after removal of solvent was treated in ethanol with ethanolic oxalic acid. The crystalline salt was recrystallised from ethanol to give 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine, bis oxalate, m.p. 130°-133° (3.05 g).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][C:7]=1[CH:15]=[O:16].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1I>>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])=[C:7]([CH:15]=[O:16])[CH:8]=1
Reactant: Brc1ccccc1I
Reactant: CN(C)CCOc1ccc(B(O)O)cc1C=O
Product: CN(C)CCOc1ccc(-c2ccccc2Br)cc1C=O
Yield: 68 %

Procedure:
General procedure G, using 4-(2-dimethylamino-ethoxy)-3-formyl-benzeneboronic acid and 1-bromo-2-iodo-benzene gave the title product as yellow oil in 68% yield. 1H-NMR (CDCl3) δ 10.51 (s, 1H), 7.90 (d, 1H), 7.70-7.65 (m, 2H), 7.41-7.20 (m, 3H), 7.09 (d, 1H), 4.40 (t, 2H), 3.04 (bs, 2H), 2.56 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:3][CH3:4].[OH-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Cl>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([NH:8][S:5]([CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:7])=[O:6])=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CCC(C)S(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)S(=O)(=O)NC(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 23.1 %

Procedure:
The general method of procedure A was followed using 2-butanesulfonamide (10 g), 1N sodium hydroxide (73 ml) and 3,4-dichlorophenyl isocyanate (13 g). 1N HCl was added and after removal of the acetone the solid was diluted with water, collected, and dried at 65° C. under vacuum. The solid was recrystallized in acetone and hexane to provide 5.2 g of product.