Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O[K])(C)(C)C.Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24].O>C1COCC1>[N:25]1([C:23](=[O:24])[CH2:22][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(CCl)N1CCOCC1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g) and tert-butoxy potassium (5.57 g) in THF (124 mL) was added 4-(chloroacetyl)morpholine (4.84 mL), and the mixture was stirred at room temperature overnight. Distilled water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solution was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained solid was washed with hexane-ethyl acetate to give the title compound (4.74 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:2].C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:3]([CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:1][CH3:2])=[O:29]
Reactant: CCNCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(=O)CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a 100 mL round bottom flask containing tert-butyl 4-((ethylamino)methyl)-4-hydroxypiperidine-1-carboxylate (2.4 g) was added dichloromethane (30 mL) and triethylamine (3 mL, 21.52 mmol). An addition funnel was attached to the flask. The vessel was placed under nitrogen and the solution was cooled to 0° C. with an ice bath. In a separate vial, chloroacetyl chloride (1 mL, 12.48 mmol) was diluted with dichloromethane (20 mL) and transferred to the addition funnel. This mixture was added dropwise to the cold starting material over 10 min. The reaction mixture was then allowed to stir under nitrogen for 3 h while slowly allowing the ice bath to warm to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and was washed with water (2×50 mL) and brine (1×50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (3.23 g) which was carried forward without further purification. MS(ES)+ m/e 335.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1COCC1>[CH:1]1([CH2:7][C:11]2([OH:10])[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH2:15][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]CC1CCCCC1
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(O)(CC3CCCCC3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of cyclohexylmethylmagnesium bromide (1.90 mL of a 2M solution in THF) at −78° C. was treated with ethyl 4-(4-oxo-1-piperidinyl)benzoate (prepared according to the procedure described in Synthesis 1981, 606-608, 0.30 g), and was allowed to warm to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 20% ethyl acetate to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:28])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[N+](=[CH2:31])=[N-]>CO.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:28])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:27]=[CH:26][CH:25]=[C:19]([O:20][CH2:21][C:22]([O:24][CH3:31])=[O:23])[CH:18]=3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (2R)-(3-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy)acetic acid (trans-H) obtained in Example 46 (1.0 g) in methanol (10 ml) there was added an excess of diazomethane in ether solution, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent under reduced pressure, separation and purification by silica gel column chromatography (ethyl acetate:hexane=5:l) gave 0.91 g of (1R)-1-(3-chlorophenyl)-2-[3-(3-methoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol (88% yield).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1COCC1>[C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc([N+](=O)[O-])c1C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
84 g of 2-methyl-3-nitroaniline is dissolved in 550 ml of THF. 53 ml of acetic anhydride is slowly added dropwise and the mixture is then stirred at 70° C. After about 1 hour, THF is distilled off and the residue is combined with 250 ml of petroleum ether. The solid precipitate is filtered off and dried at 50° C. 106 g of N-acetyl-2-methyl-3-nitroaniline is obtained as a light brown powder.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 79.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (411 mg, 0.70 mmol) prepared in Example 31a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (241 mg, 79%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]=1[F:14])[CH3:2].[C:15]1([Si:21]2(CCCC)[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)C=C[CH:18]=[CH:17][CH:16]=1>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C@H:30]2[CH2:29][CH2:28][C@H:27]([CH:24]3[CH2:23][CH2:22][SiH:21]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:26][CH2:25]3)[CH2:32][CH2:31]2)=[O:9])=[C:6]([F:13])[C:5]=1[F:14])[CH3:2]
Reactant: CCCC[Si]1(c2ccccc2)CCC(C2CCC(O)CC2)CC1
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Product: CCCC[SiH]1CCC([C@H]2CC[C@H](OC(=O)c3ccc(OCC)c(F)c3F)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-ethoxy-2,3-difluorobenzoic acid and 4-(4-phenyl-4-n-butyl-4-silacyclohexyl)cyclohexanol, thereby obtaining the intended product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](O)([CH:8]([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:4]([F:7])([F:6])[F:5].[F:20]C(F)(F)C(F)=C(F)F.CN(C)C.F>O1CCCC1>[F:1][C:2]([F:19])([F:18])[CH:3]([C:8]([F:20])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:4]([F:7])([F:6])[F:5]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: OC(C(F)C(F)(F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: CN(C)C
Agent: F
Solvent: C1CCOC1
Product: FC(F)(F)C(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
To prepare 2-trifluoromethyl-1,1,1,3,4,4,5,5,5-nonafluoro-2-pentanol, commercially available hexafluoropropene may be oligomerized with commercially available trimethylamine in a dipolar aprotic solvent such as commercially available tetrahydrofuran to provide (CF3)2C:CFCF2CF3 which is then reacted with commercially available hydrogen fluoride to yield 2-trifluoromethyl-1,1,1,3,3,4,4,5,5,5-decafluoropentane as taught by W. Brunskill et al., "Anionic Oligomerisation of Hexafluoropropene: Fission of a Carbon-Carbon Bond by Fluoride Ion", Chemical Communications, 1444 (1970). The 2-trifluoromethyl-1,1,1,3,3,4,4,5,5,5-decafluoropentane may then be dehydrohalogenated and then reacted with sulfuric acid and then water to form 2-trifluoromethyl-1,1,1,3,4,4,5,5,5-nonafluoro-2-pentanol.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:7])[F:8]
Reactant: O=C(Nc1ccc(CCO)cc1Cl)C(F)(F)F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(CCOC2CCCCO2)cc1Cl)C(F)(F)F

Procedure:
To a solution of 2′-chloro-4′-(2-hydroxyethyl)-2,2,2-trifluoroacetanilide (1.4 g) and 3,4-dihydro-2H-pyran (1.4 ml) in dichloromethane (15 ml) was added pyridinium p-toluenesulfonate (14 mg), and the mixture was heated under reflux for 1 hour with stirring. After concentration of the reaction mixture in vacuo, the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=3/1) gave 2′-chloro-4′-[2-((RS) -tetrahydropyran-2-yloxy)ethyl]-2,2,2-trifluoroacetanilide (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7].[H-].[Na+].[CH2:32](Cl)[C:33]#[CH:34]>CN(C=O)C>[CH2:34]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:24])[C:33]#[CH:32]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)CCc2cc(N3CCN(C(=O)c4ccc(OC)c(OC)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
6-[4-(3,4-Dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (1.96 g) and 0.25 g of 50% oily sodium hydride were mixed with 60 ml of DMF and stirred at room temperature for 2 hours. Then, to the mixture was added 0.66 g of propargyl chloride and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into a 150 ml of saturated saline solution and organic substances were extracted with chloroform. The chloroform layer was washed with water and dehydrated. Chloroform was distilled off and the residue was purified through silica gel column chromatography followed by recrystallization from ethanol to give 0.34 g of 1-(2-propynyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 152°-154° C., pale yellow needles.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:10][OH:11])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH:13]([CH3:17])[C:14](Cl)=O.C(N(CC)CC)C>CC(C)=O>[CH2:7]([C:8]1[N:9]=[C:14]([CH:13]([Cl:12])[CH3:17])[O:11][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: NC(Cc1ccccc1)=NO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(Cl)c1nc(Cc2ccccc2)no1
Temperature: 0 °C
Yield: 95.2 %

Procedure:
First, 15.0 grams (0.1 mole) of phenyl acetamide oxime was combined with 100 milliliters of dry acetone in a 250 milliliter flask fitted with a thermometer and dropping funnel. The solution was stirred and cooled to 0° C. Next, 12.7 grams (0.1 mole) of 2-chloro propionyl chloride and 10.1 grams (0.1 mole) of triethyl amine was added. During the additions, the temperature was maintained at 0 to 5° C. After the additions were complete, the reaction mass was stirred at room temperature for 30 minutes and then was filtered free of salt. The filtrate was evaporated in vacuo at 50° and the residue was taken up in 300 milliliters of toluene. The toluene solution was charged to a 500 milliliter flask fitted with a Dean Stark water trap, 0.1 gram of toluene sulfonic acid was added, and the solution was heated under reflux until water ceased to be evolved. The toluene solution was then treated with activated carbon, filtered and evaporated in vacuo at 50° C. to yield 21.2 grams (95% of theory) of 3-benzyl-5-(1-chloroethyl)1,2,4-oxadiazole. nD30 1.5040.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:13]=1.Cl>C1COCC1>[CH2:14]([C:11]1[S:10][C:9]([C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Brc1cccs1
Reactant: CCCCCCCCCCc1ccc(Br)s1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65934.5 %

Procedure:
Magnesium (8.90 g, 0.365 mmol) and THF (100 ml) were placed in a 300-ml flask equipped with a reflux tube. A solution of 2-bromothiophene (54.0 g, 0.332 mmol) in THF (100 ml) was slowly added drowpwise thereto, and the mixture was heated under reflux for about 2 hr to prepare a Grignard reagent. This Grignard reagent was added dropwise to a mixed solution composed of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (1.80 g, 2.21 mmol), 2-bromo-5-decylthiophene (67.0 g, 221 mmol) prepared above, and THF (100 ml) at about 0° C. After the completion of the dropwise addition, the mixture was stirred at room temperature overnight. After the completion of the reaction, 1 N HCl (200 ml) was added to the reaction solution, and the organic layer was extracted with chloroform, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 5-decyl-2,2′-bithiophene as a light yellow solid (67.1 g, yield 99.1%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.31 (m, 14H), 1.67 (m, 2H), 2.78 (t, 2H, J=7.32 Hz), 6.67 (d, 1H, J=3.90 Hz), 6.98 (m, 2H), 7.09 (d, 1H, J=3.90 Hz), 7.15 (d, 1H, J=4.88 Hz)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:15]1[C:14]2[CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[CH2:11][O:12][C:13]=2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16]=1[NH2:21]
Reactant: Cc1c(N)cc2c(c1C)OCC2c1ccc(C(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1c(C)c2c(c(Br)c1N)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine synthesized in Reference Example 31 (5.62 g, 21.1 mmol) in acetonitrile (60 mL), was added N-bromosuccinimide (3.76 g, 21.1 mmol) at −20° C., and the mixture was stirred at the same temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 0.90 g (yield 34%) of the title compound. Melting point: 191-193° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)(=[O:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)NCC1CNCCO1

Procedure:
2-Acetylaminomethyl-4-benzylmorpholine (120 g) is dissolved in a mixture of ethanol (1000 ml) and acetic acid (30 ml) and hydrogenated over 10% palladium on carbon (5 g) at about 60° C. After the calculated amount of the hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound as an oil.
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:2].[CH:8]([C:11]1OC(=O)[S:13][N:12]=1)([CH3:10])[CH3:9]>CC1C=CC(C)=CC=1>[CH:8]([C:11]1[N:2]=[C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:13][N:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nsc(=O)o1
Reactant: CCOC(=O)C#N
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1nc(C(C)C)ns1
Yield: 96.8 %

Procedure:
Ethyl cyanoformate (38.6 g, 0.39 mol) is added to a stirred solution of 5-isopropyl-[1,3,4]oxathiazolin-2-one (18.5 g, 0.13 mol) in p-xylene (180 ml). The mixture is refluxed for 6 hours and then the solvent is evaporated in vacuo to give crude ethyl 3-isopropyl-[1,2,4]thiadiazole-5-carboxylate (25.2 g, 97%) as a yellow oil, which is used without purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[O:30][N:29]=[CH:28][C:27]=1[C:31](Cl)=[O:32]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:27]5[CH:28]=[N:29][O:30][C:26]=5[CH3:25])=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1oncc1C(=O)Cl
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Solvent: CN1CCCC1=O
Product: Cc1oncc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 51.3 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), N-methylpyrrolidone (5 mL) and 5-methylisoxazole-4-carbonyl chloride (146 mg, 1.00 mmol), and in the same manner as in Example 162, the title compound (112 mg, yield 51%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:23]=[C:22]([C:24]([O:26]C)=[O:25])[NH:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[NH:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(-c2cc(Cl)c(OCc3ccc(OC)cc3)c(Cl)c2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(COc2c(Cl)cc(-c3cc(C(=O)O)[nH]n3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a mixture of methyl 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-1H-pyrazole-5-carboxylate (0.75 g, 1.85 mmol) in a mixture of THF (10 mL) and methanol (10 mL) was added 15% w/v solution of sodium hydroxide (5 mL). The mixture was stirred at room temperature for 30 minutes followed by heating at reflux for 2 h. After this time the flask was cooled to room temperature and solvent was removed in vacuo. The residue was partitioned between ethyl acetate (20 mL) and water (100 mL). The aqueous layer was acidified to pH 1 (10 M HCl, 1.5 mL) and the precipitated solids dissolved in ethyl acetate (30 mL). The organic layer was washed with an aqueous solution of sodium chloride (65 mL) and dried (MgSO4). The solution was concentrated to give 0.69 g (96%) of the Compound C as a white solid. 1H NMR δ (ppm) (DMSO-d6): 3.81 (3H, s), 5.02 (2H, s), 7.00 (2H, d, J=8.24 Hz), 7.41 (1H, s), 7.48 (2H, d, J=8.24 Hz), 8.03 (2H, s), 14.09 (1H, br s). CO2H peak not observed.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[C@@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:26][C:2]1([CH3:1])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N:18]4[C:19](=[O:25])[C@@H:20]([CH:22]([CH3:23])[CH3:24])[NH:21][C:28]4=[O:30])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC(C)[C@@H](N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)N(c2cnc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of N1-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-D-valinamide (Intermediate 145, 38 mg, 0.107 mmol) in dry Dichloromethane (DCM) (5 mL) TEA (0.074 mL, 0.533 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (14.24 mg, 0.048 mmol) in dry Dichloromethane (DCM) (1 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (3 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column SNAP 25 g and cyclohexane/ethyl acetate from 8:2 to 1:1 as eluent affording the title compound (15 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])=[O:4].CN(C)C=O.[H-].[Na+].Cl[C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:21]=1>C(Cl)(Cl)Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:22]2[N:21]=[C:20]([O:1][CH2:2][C:3]([N:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])=[O:4])[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[N:23]=2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(-c2nc(Cl)c3c(n2)CCCC3)cc1
Reactant: CCCN(CCC)C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)C(=O)COc1nc(-c2ccc(F)cc2)nc2c1CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a mixture of 2-hydroxy-N,N-dipropylacetamide (1.8 g) and dimethylformamide (20 ml) is added sodium hydride (about 60% oily, 0.5 g) at 0 to 5° C., and the mixture is stirred at 0° C. for one hour. To the reaction mixture is added 4-chloro-2-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (2.0 g) at the same temperature, and the mixture is stirred at room temperature for four hours. To the mixture are added chloroform and ice-water, and the chloroform layer is collected, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from a mixture of diethyl ether and n-hexane to give the desired compound (2.2 g), m.p. 95-96° C.