Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([Br:15])[CH2:12][CH2:13]Br>CN(C)C=O>[Br:15][CH:11]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[CH2:12][CH2:13][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCCC(Br)Oc2ccccc2)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
In a stream of nitrogen, 100 ml of a dimethylformamide (to be referred to as DMF hereinafter) solution containing 20.03 g (115.8 mmol) of 3-bromophenol was cooled to 5° C. and mixed with 4.9 g (122 mmol) of 60% sodium hydride. After 1 hour of stirring at room temperature, this was mixed with 25 ml of a DMF solution containing 11.5 g (57 mmol) of trimethylene dibromide and stirred at 70° C. for 20 hours. The reaction solution was extracted with 800 ml of ethyl acetate and washed with water (200 ml, 5 times) and saturated brine (100 ml, twice). The organic layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the residue by a silica gel column chromatography, 13.70 g (yield 62%) of the title compound was obtained as a colorless oil.
Reaction SMILES: C([NH:8][C:9]1[C:10]([Cl:37])=[C:11]([N:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:28])[O:26][CH3:27])[C@@H:20]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:19]2)[CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)CCl>[NH2:8][C:9]1[C:10]([Cl:37])=[C:11]([N:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:28])[O:26][CH3:27])[C@@H:20]([O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:31])[CH3:32])[CH2:19]2)[CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1
Reactant: COC(=O)N[C@H]1CCN(c2cc(C(N)=O)cc(NC(=O)OC(C)(C)C)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)N[C@H]1CCN(c2cc(C(N)=O)cc(N)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
methyl ((3S,4S)-1-(3-(N-BOC-amino)-5-carbamoyl-2-chlorophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (125 mg, 0.168 mmol) was dissolved in ClCH2CH2Cl (10 ml). Trifluoroacetic acid (3 ml, 38.9 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours, and then evaporated to dryness. The crude was purified by column chromatography on silica (40 g cartridge, gradient from 100% DCM to 100% EtOAc, then hold at 100% EtOAc) to give methyl ((3S,4S)-1-(3-amino-5-carbamoyl-2-chlorophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (67 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)OCC)C>>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[CH:17][N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[C:4]2=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1nnn[nH]1
Product: O=c1c2cc(Cl)ccc2ncn1-c1nnn[nH]1

Procedure:
A suspension of 2.73 g of 2-amino-5-chloro-N-(1H-tetrazol-5-yl)benzamide in 9 ml of triethoxymethane was refluxed for 4.5 hours to give 6-chloro-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 241° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=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.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: c1ccc(COc2ccc(CCOC3CCCCO3)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of 1-benzyloxy-4-(2-hydroxyethyl)benzene (7, 20 g, 87.7 mmoles) in CH2Cl2 (175 mL) was added 4-toluenesulfonic acid (TsOH, 0.17 g, 0.9 mmoles) and dihydropyran (9.9 mL dropwise, 108 mmoles). The mixture was stirred for 4 h and the solvent evaporated under reduced pressure to yield 28 g of crude product. This was purified by flash chromatography (solvent=70:30 ethyl acetate:heptane). The pure fractions were pooled and the solvent evaporated to give 1-benzyloxy-4-(2-tetrahydropyran-2-yloxyethyl)benzene (8, 26.5 g). NMR (CDCl3)δppm: 7.30(s, 5H); 6.97(q, 4H); 4.95(s, 2H); 7.87(s, 1H); 4.2-3.4(m, 4H); 2.8(t, 2H); 1.9-1.3(m, 6H). (Scheme II, Step 3.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([NH:13][CH2:14][C:15]([O:17]CC)=O)=[O:12].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH3:24][CH:23]([N:13]1[CH2:14][C:15](=[O:17])[N:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[C:11]1=[O:12])[CH3:25]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(OC)cc1F
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)CN(C(C)C)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 17.02 g (0.0630 mole) of N-(2-fluoro-4-methoxyphenyl-N'-ethoxycarbonylmethylurea in 50 mL of N,N-dimethylformamide was added dropwise to a suspension of 2.65 g (0.0662 mole) of sodium hydride in 30 mL of N,N-dimethylformamide during a 20 minute period. Gas evolution and a slight rise in temperature occurred during the addition. This mixture was stirred at room temperature for 45 minutes, by which time it had become a homogeneous solution. To this solution was added dropwise, over a period of 15 minutes, a solution of 21.42 g (0.126 mole) of 2-iodopropane in 10 mL of N,N-dimethylformamide. The temperature rose to 38° C. during the addition period. This reaction mixture was stirred for approximately 65 hours, then poured over ice and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving an orange oil as a residue. This oil was placed on a silica gel column and eluted sequentially with 97.5/2.5 and 95/5 mixtures of methylene chloride and ethyl acetate. After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 5.85 g of 1-(1-methylethyl-3-(2-fluoro-4-methoxyphenyl)imidazolidin-2,4-dione was isolated as an orange solid, m.p. 88°-90° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15](F)=[N:16][CH:17]=1.Cl>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:16][CH:17]=1
Reactant: Oc1ccc(O)cc1
Reactant: Fc1cc(Cl)cnc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 27.5 g (0.25 mol) of hydroquinone, 11.2 g (0.2 mol) of potassium hydroxide in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere until everything is dissolved. A solution of 30 g (0.2 mol) of 5-chloro-2,3-difluoropyridine in 200 ml of dimethylsulfoxide is added dropwise thereto. The reaction mixture is then heated to 70° and stirred at that temperature for 4 hours. Then it is poured into ice/water and the mixture is acidified with hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is taken up in a hexane/ethyl acetate 2:1 solvent and passed over a silicagel column for purification. After concentrating the eluate, the residue crystallizes to yield 33 g of white crystals, melting at 97°-98° .
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+:22]>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[K+:22]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Reaction time: 2 h

Procedure:
In a 2-liter beaker equipped with a stirrer were placed 141 g of oleic acid (acid value: 198), 59 g of a 48% aqueous solution of caustic potash and 1406 g of water. A reaction was carried out for 2 hours at 30° C. with stirring to obtain an aqueous solution of potassium oleate having a pH value of 10.4 and containing 10.1% by weight of a solid matter.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35](Br)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[N:8][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (180 mg, 63%). MS (ISN) 568.2 [(M−H)−]; mp 170° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][C:11]1=[O:23])[CH2:5][C:6]([F:9])([F:8])[F:7].O1CCCC1.O.[OH-].[Li+]>O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([CH:4]([CH2:5][C:6]([F:9])([F:8])[F:7])[C:3]([OH:24])=[O:2])[C:11](=[O:23])[CH:12]=1
Reactant: COC(=O)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.5 %

Procedure:
A mixture of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid methyl ester (212 mg, 0.58 mmol) in a 1:1 solution of tetrahydrofuran:water (8 mL) was treated with lithium hydroxide monohydrate (55 mg, 1.16 mmol) and stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and then diluted with water (10 mL) and the pH adjusted to pH=4 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layers were then dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid (149 mg, 73%) as a white solid: HR-ES-MS m/z calculated for C14H11NO4ClF3 [M+Na]+ 372.0221, observed 372.0224.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:30][CH:31]=1
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(/C=C/c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1

Procedure:
Trifluoroacetic acid 10 mL solution of the obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and ethyl acetate and saturated sodium thiosulfate aqueous solution were added to the obtained residue. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure to give 2-(4-fluoroanilino)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic acid 28 mg of pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([CH2:30][NH:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=4)[N:35]=[CH:34][CH:33]=3)=[N:28][N:29]=2)[N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][NH:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[N:26]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18]
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: CC(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(C(C)O)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (228 mg, 807 μmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (197 mg, 576 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (127 mg, 173 μmol), cesium carbonate (751 mg, 2306 μmol) in dioxane (3 mL) and water (0.6 mL) was sparged with argon for 5 min then heated to 100° C. for 6 h. Reaction cooled then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (15 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). The combined organics dried over MgSO4. concentrated, then purified on 40 g silica eluting with an isocratic 7% 2M NH3 in MeOH/DCM. Product further purified prep HPLC eluting with water/ACN (0.1% TFA). After collected fractions were reduced to a clear the residue was dissolved in 1:1 ACN/water and pH adjusted to 9 with 1M NaOH (3-4 drops). Resulting solid collected by filtration and solid washed with water (2 mL). MS (ESI pos. ion) m/z: 462 (MH+). Calc'd exact mass for C23H20ClN7O2: 461.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]([O:12][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])([CH3:10])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](OC(C)(C)c1cc(F)cc(F)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)ethanone (1.0 equiv) in THF (0.2 M) at 0° C. was added methylmagnesium bromide (1.0 M in THF, 1.15 equiv). After stirring for 4 hours the reaction was quenched by addition of NH4Cl(sat.), diluted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield 2-(3,5-difluorophenyl)propan-2-ol. To a solution of 2-(3,5-difluorophenyl)propan-2-ol in CH2Cl2 (0.1 M) at 0° C. was added 2.6 lutidine (6 equiv.) and than triisopropylsilyl trifluoromethanesulfonate (3.0 equiv.). After stirring for 3 hours at 0° C. and six hours at rt the solution was partitioned between EtOAc and NaHCO3(sat.), separated, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane. (400 MHz, <cdcl3>) δ ppm 1.05-1.08 (m, 21H) 1.57 (s, 6H) 6.63 (s, 1H) 7.00 (dd, J=9.39, 2.35 Hz, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)=[O:17]
Reactant: c1ccc2c(c1)OCCO2
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)c1ccc2c(c1)OCCO2

Procedure:
Using 2,3-dihydro-1,4-benzodioxine. (10.0 g) and 5-chlorovaleryl chloride (10.4 ml) according to the same method as that, of Reference Example 1, the title compound was obtained as colorless crystals (15.1 g) having a melting point of 52 to 53° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[C:25]([OH:27])=O)[CH2:3][CH2:2]1.[N:28]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[C:25]([N:36]2[CH2:37][CH2:38][CH:33]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:34][CH2:35]2)=[O:27])[CH2:3][CH2:2]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1c(-c2cccnc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Product: O=C(c1c(-c2cccnc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1)N1CCC(N2CCCC2)CC1
Yield: 70 %

Procedure:
In analogy to the procedure described in Example 160E], 5-cyclopropyl-3-pyridin-3-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave the title compound as a light yellow solid (70%). MS: 510.4 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:14]=[N:13]2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:14]=[N:13]2)[C:9]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 98 %

Procedure:
Using the method described in Example 49, 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 33) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (2.0 g, 98%); ES+-HRMS m/e calcd for C26H31N5O4F2 [M+H+] 516.2417 found 516.2417. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.26 (m, 6H) 1.03 (s, 3H) 1.04 (s, 3H) 1.45-1.70 (m, 5H) 1.73-1.91 (m, 1H) 2.01-2.24 (m, 1H) 3.87 (s, 2H) 4.66 (s, 1H) 5.52 (dd, J=11.0, 4.1 Hz, 1H) 6.02 (d, J=2.7 Hz, 1H) 6.37 (d, J=2.2 Hz, 1H) 7.24-7.49 (m, 3H) 7.51 (d, J=2.2 Hz, 1H) 8.27 (d, J=2.7 Hz, 1H) 10.83 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10](OCC)=[O:11])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[NH2:19][NH2:20]>CO>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9]([C:10]([NH:19][NH2:20])=[O:11])=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1
Reactant: NN
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NN)CC(C)(C)N1

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-aminooxamide was prepared by the hydrazinolysis of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate with 64% aqueous hydrazine in methanol.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:21][CH2:22][CH3:23])[NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[O:12]1)#[N:2].[ClH:24].CC([OH:28])C>CO>[ClH:24].[ClH:24].[O:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][CH:11]1[CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]([NH:21][CH2:22][CH3:23])=[N:3][C:1]([NH2:2])=[O:28]
Reactant: CCNC(=NC#N)NCCCNCC1CCc2ccccc2O1
Reactant: CC(C)O
Agent: Cl
Solvent: CO
Product: CCNC(=NC(N)=O)NCCCNCC1CCc2ccccc2O1

Procedure:
A mixture of 3.1 g (±)-N"-cyano-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N'-ethylguanidine in a solution of 10 ml hydrochloric acid in 2-propanol and 50 ml methanol was stirred and refluxed for 30 minutes. The solvent was evaporated. The residue was dissolved in water and this mixture was alkalized with aqueous NaOH (10%). This mixture was extracted with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/(NH3) 90:10). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:2) with 2-propanol saturated with HCl. The salt was filtered off and recrystallized from 2-propanol. The crystals were filtered off and dried, yielding 2.95 g (±)-N-[[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]amino](ethylamino)methylene]urea dihydrochloride; mp. 182.2° C. (interm. 51).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]1[CH3:33])=[O:4].[CH3:34][CH:35]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])=[N:42][CH:43]=1)[CH3:36]>>[F:24][C:22]([F:25])([F:23])[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:41]4[CH:40]=[CH:39][C:38]([O:37][CH:35]([CH3:34])[CH3:36])=[CH:43][N:42]=4)([CH3:51])[NH:48][C:47]3=[O:49])[C@H:6]([CH3:33])[CH2:7]2)=[C:12]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([OH:26])[C:18]([F:19])([F:21])[F:20]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@H](C)C1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)[C@H](C)C1

Procedure:
(R)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [C:1]([NH:6][CH:7]([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:14](OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:8]([CH:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:11][CH:12]=[CH2:13])(=[O:10])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC(NC(=O)C(C)C)C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: C=CCC(NC(=O)C(C)C)C(C)=O

Procedure:
7.77 g of the above synthesized 2-isobutyrylamino-pent-4-enoic acid (41.95 mmol) were dissolved in 36.5 ml of pyridine, treated with 19.83 ml of acetic anhydride (5 eq.), and heated to 100° for 1 h. After cooling, 28.3 ml of water were added and the mixture kept for 20 Min. at 90°. Careful pouring onto crashed ice/HCl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=1/1) left finally 6.63 g of the title compound as yellowish oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[C:17]1([C:11]2([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2)CCNCC1

Procedure:
1-tert-Butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid amide (0.95 g, 3.12 mmol) was combined with HCl in dioxane (10 mL, 4N, 40 mmol, 13 eq.) at ambient temperature for 1 h. The solvent was concentrated in vacuo and ethyl acetate was added. The slurry was filtered and dried under high vacuum for 48 h to give the title compound: HPLC analysis Rt =5.56 min. using a C-18 column eluting with a acetonitrile:water (0.1% TFA), flow rate=1.0 mL/min., gradient (elution with CH3CN/H2O(0.1%TFA) 10% CH3CN for 10 minutes, 30% CH3CN for 15 minutes, 40% CH3CN for 15 minutes, 50% CH3CN for 10 minutes, and then 100% CH3CN). Analysis: calculated for Cl2H17C1N2O C 59.87; H 7.12; N 11.64; Found C 59.82; H 7.00; N 11.52.