Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24]([CH:25]=[O:26])=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20]4[C:24]([CH2:25][OH:26])=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:33][CH:34]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g) in tetrahydrofuran (5 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.040 g) at 0° C. After stirring the reaction mixture at room temperature for 1 hr, water was added, and the precipitated crystals were collected by filtration to give [3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]methanol as colorless crystals (0.50 g, yield 98%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[S:31][C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:29][C:28]=12)=[O:22]>O1CCCC1>[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[S:31][C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:7](=[O:9])[C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])[CH2:34][CH2:33]3)=[N:29][C:28]=12)=[O:22]
Reactant: COC(=O)c1cccc2sc(N3CCNCC3)nc12
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cccc2sc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)nc12

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 2-Piperazin-1-yl-benzothiazole-4-carboxylic acid methyl ester hydrochloride in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:22]=[C:23]([Cl:25])[N:24]=2)[C:18]([O:20][CH3:21])=[O:19])[CH2:11][CH2:10]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:25].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[C:17]([CH:22]=[C:23]([Cl:25])[N:24]=2)[C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 200 %

Procedure:
Methyl 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6-chloroisonicotinate (Intermediate 23, 1.81 g, 4.9 mmol) was dissolved in 4 N HCl/dioxane (200 ml). The mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum to give the title compound (1.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.C(OCC)(=O)C.[OH-].[Na+].[Br:40]Br>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:11]([C:17]([NH:18][CH:19]([CH:21]3[CH2:23][CH2:22]3)[CH3:20])=[O:24])=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=2[Br:40])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixed solution comprising 6.0 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide and 75 ml of ethyl acetate was cooled with ice, 1.4 g of sodium hydroxide (flakes) was added, and then 2.8 g of bromine was added over a period of 2 hours. After stirring at room temperature for 18 hours, 60 ml of water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with 20 ml of a mixed solution of ethyl acetate and hexane (1:5) and subjected to filtration to obtain 6.2 g of the desired product in the form of white crystals.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(I)c4c3)o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: -25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
To a solution of 5-(3-iodo-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.5 g, 1.12 mmol) in DMF (5 mL) at −25° C. was added NaH (0.059 g, 50% in mineral oil, 1.23 mmol) portion wise. The mixture was stirred for 5 min at −25° C. then a solution of 4-methyl benzene sulfonyl chloride (0.235 g, 1.23 mmol) in DMF (1 mL) was added at same temperature dropwise. The reaction was stirred at −25° C. for 10 min. The mixture was poured into ice cold water and a white solid precipitated out which was collected by filtration and recrystallized by triturating it with 1:3 volume of EtOH (2 mL) and CHCl3 (6 mL) to give 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.450 g, 0.75 mmol, 66.96%). MS (ESI, pos. ion) m/z: 601.1 (M+1); 1H-NMR (DMSO-d6) δ8.312 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.9-7.90 (m, 3H), 7.68 (s, 1H), 7.44 (d, J=9 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 4.38 (d, J=6 Hz, 2H), 3.73 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O.O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:32][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2F)cs1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CCl)cc2F)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
To a solution of N-(4-{2-[2-fluoro-4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (194.7 mg, 0.665 mmol) in anhydrous dichloromethane (2 ml) were added triethylamine (0.17 ml, 1.20 mmol) and 4-dimethylaminopyridine (8.1 mg, 0.066 mmol), and the mixture was cooled to 0° C. Methanesulfonyl chloride (77 μl, 1.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The mixture was cooled to 0° C., triethylamine (93 μl, 0.67 mmol) and methanesulfonyl chloride (51 μl, 0.67 mmol) were added, and the mixture was stirred at room temperature for 5 min. Iced water (2 ml) was added to the reaction mixture, and the mixture was stood still and partitioned. The aqueous layer was extracted 3 times with dichloromethane, and the combined organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Merck 9385 16 g, ethyl acetate:hexane=2:3) to give N-(4-{2-[4-(chloromethyl)-2-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (59.6 mg, 0.191 mmol, yield 28.7%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)=[O:14].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:12]/[C:13]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: CCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a stirred solution of 4-ethoxybenzaldehyde (1.0 g, 6.6 mmol) and 3,5-dimethoxyacetophenone (1.19 g, 6.6 mmol) in methanol (10 ml) was added 50% w/v of aqueous sodium hydroxide (5.3 ml, 0.06 mol). The reaction mixture was stirred for 2 h at room temperature and then extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over magnesium sulphate and reduced in vacuo and the product was recrystallised from ethanol to give 1.12 g (74%) of yellow crystals. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.3 (d, 1H), 7.15 (d, 2H), 6.9 (d, 2H), 6.65 (t, 1H), 4.0 (q, 2H), 3.8 (s, 6H), 1.4 (t, 3H). 13C-NMR (CDCl3) δ 190.1, 161.1, 160.8, 140.6, 127.4, 63.6. Mass Spectrum m/e (M+1) 313.
Reaction SMILES: C[B-](F)(F)[F:3].[K+].[CH3:7][Si:8]([C:11]#[N:12])([CH3:10])[CH3:9]>>[CH3:7][Si:8]([C:11]#[N:12])([CH3:10])[CH3:9].[CH3:7][Si:8]([CH3:11])([CH3:9])[F:3]
Reactant: C[B-](F)(F)F
Agent: C[Si](C)(C)C#N
Agent: [K+]
Product: C[Si](C)(C)F
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Potassium methyltrifluoroborate, K[CH3BF3] (500 mg, 4.10 mmol), is suspended in trimethylsilyl cyanide (20 ml, 149.9 mmol). The reaction mixture is stirred at 50° C. for 2 days and subsequently at 80° C. for 24 hours. Excess trimethylsilyl cyanide and trimethylfluorosilane formed are distilled off and can be employed for further reactions. A slightly reddish solid is obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Li]CCCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1>C1COCC1>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: OCc1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1ccccc1C1(O)CCC2(CC1)OCCO2
Temperature: -4 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromobenzyl alcohol (3.0 g, 16 mmol) in THF (40 mL) cooled at −78° C. was added a 2.5 M solution of n-BuLi in hexanes (14.1 mL). The mixture was stirred at −4° C. for 1 hour and cooled back to −78° C. To it was added a solution of 1,4-cyclohexanedione mono-ethylene ketal (2.5 g, 16 mmol) in THF (10 mL) over 15 minutes. Stirring was continued at −78° C. for 30 minutes and at −4° C. for 1 hour. The reaction was quenched by addition of a solution of NH4Cl in water. The resulting solution was extracted with EtOAc three times. The combined extract was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5% MeOH/CH2Cl2 provided the title compound. MS calculated (M+H)+ 265, found 287 (M+Na)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([O:16][C:17]2[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13]1)=[O:11].[C:24]([Si:28]([CH3:46])([CH3:45])[O:29][CH:30]1[CH2:35][CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH2:31]1)([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([O:16][C:17]2[C:22]([C:33]3[CH2:34][CH2:35][CH:30]([O:29][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:45])[CH3:46])[CH2:31][CH:32]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13]1)=[O:11]
Reactant: CC1(C)OB(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)OC1(C)C
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(Oc2nccnc2Cl)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2nccnc2OC2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 120 °C
Yield: 163.8 %

Procedure:
A glass microwave vessel was charged with (1H-benzo[d]imidazol-2-yl)(3-(3-chloropyrazin-2-yloxy)azetidin-1-yl)methanone (see PREPARATION P23.1; 219 mg, 0.664 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyloxy)silane (366 mg, 1.082 mmol, purchased from Small Molecules Inc.), sodium carbonate (211 mg, 1.992 mmol), and dioxane:water (10:1, 15 mL). The solution was purged with N2 for 5 minutes, then palladium tetrakis (153 mg, 0.133 mmol) was added. The reaction mixture was stirred and heated in a Biotage Initiator at 120° C. for 60 minutes. The reaction was poured into water (30 mL) and extracted with EtOAc (2×20 mL). The combined EtOAc layers were eluted through a plug of silica gel. The filtrate was concentrated in vacuo to give crude (1H-benzo[d]imidazol-2-yl)(3-(3-(4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)pyrazin-2-yloxy)azetidin-1-yl)methanone (550 mg, 164% yield), as a yellow solid. The product was carried forward in the next step without further purification. MS (ESI) m/z 506.3 (MH+).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17]([NH:19]C(=O)C4C=CC=CC=4)=[S:18])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[OH-].[K+].CO.O1CCCC1>C(OCC)(=O)C.O>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(=S)NCc1ccc2c(c1)Nc1nccnc1S2)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: NC(=S)NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 50 °C
Yield: 76.1 %

Procedure:
250 mg of N-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N′-benzoylthiourea was added to a mixture of a 20% aqueous solution of potassium hydroxide (5 ml) with methanol (5 ml). After further adding a small portion of tetrahydrofuran, the resulting mixture was heated to 50° C. for 5 minutes. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were suspended in ethyl acetate and filtered. Thus, 140 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [CH2:1]([C:8]([CH2:10][CH3:11])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH:15]=[CH2:16]>>[C:2]1([CH:1]([C:8](=[O:9])[CH2:10][CH3:11])[CH2:16][CH2:15][CH:14]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)Cc1ccccc1
Reactant: C=CCCBr
Product: C=CCCC(C(=O)CC)c1ccccc1

Procedure:
Ethyl benzyl ketone is reacted with 1-bromo-3-butene according to the foregoing details and there is obtained 5-phenyl-oct-1-en-6-one of boiling point 106° C./4 mmHg; nD20 =1.5088.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[S:16][C:17]=3[C:18]#[N:19])[CH:10]=[N:9]2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].O>C(O)(C(F)(F)F)=O>[NH:8]1[CH:12]=[C:11]([C:13]2[N:14]=[C:15]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[S:16][C:17]=2[C:18]#[N:19])[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3C#N)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1sc(Nc2ccccn2)nc1-c1cn[nH]c1
Yield: 25.8 %

Procedure:
According to Scheme 5 Step 3: A solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-ylamino)thiazol-5-carbonitrile (0.93 mmol, 360 mg) in TFA (3 mL) was microwaved for 5 min at 140° C. The reaction mixture was neutralized with a saturated solution of Na2CO3 (40 mL) and water (50 mL). The aqueous phase was filtered to afford a brown solid which was recrystallized thrice with DMF/water to yield 4-(1H-pyrazol-4-yl)-2-(pyridin-2-ylamino)thiazol-5-carbonitrile (0.24 mmol, 65 mg, 26%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH:26]([CH3:28])[CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25].S(Cl)(Cl)=O.[NH3:34]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH:26]([CH3:28])[CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:20])[NH2:34])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1cc(C(=O)O)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Reactant: N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCc1cc(C(N)=O)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Reaction time: 1 h

Procedure:
A mixture comprising 168 mg of 4-chloro-5-[3-(2-n-butyl-4-carboxyphenoxy)propylamino]-2-i-propyl-3(2H) pyridazinone (Compound No. 112), 119 mg of thionyl chloride and 10 ml of dried tetrahydrofuran, was refluxed under stirring for 1 hour. The reaction mixture was subjected to distillation under reduced pressure. To the residue, 20 ml of dried benzene was added. The mixture was again subjected to distillation under reduced pressure to remove excess thionyl chloride by azeotropic distillation. The residual oily substance thereby obtained, was dissolved in 10 ml of dried tetrahydrofuran, and ammonia gas was introduced thereinto for 5 minutes under cooling with ice. Then, the reaction solution was further stirred for 15 minutes. The reaction mixture was subjected to distillation under reduced pressure, and water was poured into the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed sequentially with a 5% sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off, and a pale yellow oily substance thereby obtained was crystallized from methanol-ethyl ether to obtain 143 mg of the above identified compound as colorless crystals having a melting point of 172° to 174° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19]Br)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:21]=[N+:22]=[N-:23].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][N:21]=[N+:22]=[N-:23])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(CBr)cc(-c2cccc(C#N)c2)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CN=[N+]=[N-])cc(-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In 33 ml of dimethylformamide, was dissolved 1.1 g of the compound obtained in Example 5. To the resulting solution, was slowly added 325 mg of sodium azide. The obtained reaction solution was stirred at room temperature for 2 hours, and 80 ml of water and 120 ml of ethyl acetate were then added thereto to extract organic substances. The aqueous layer was extracted with 100 ml of ethyl acetate twice. The resulting extract was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 925 mg (95%) of the title compound as a light-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[OH:24].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[O:24][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.59 g (0.0525 moles) of 2-chloro-5-nitrobenzonitrile, 9.96 g (0.0541 moles) of 2,3,4,5,6-pentafluorophenol, 7.56 g (0.0541 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of deionized water. The product separated as a crystalline solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 200 ml of absolute ethanol to give 9.91 g (57% yield) of purified 2-(2,3,4,5,6-pentafluorophenoxy)-5-nitrobenzonitrile, mp 127.5°-129° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH3:11]I.[CH2:13]([O:16][C:17]1[CH:38]=[CH:37][C:20]([CH:21]=[CH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:27][CH2:26]2)=[O:24])=[CH:19][C:18]=1[O:39][CH3:40])[CH:14]=[CH2:15].[Cl-].[NH4+]>C1COCC1>[CH2:13]([O:16][C:17]1[CH:38]=[CH:37][C:20]([CH:21]=[CH:22][C:23]([N:25]2[CH2:26][CH2:27][C:28]([CH3:11])([C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:29][CH2:30]2)=[O:24])=[CH:19][C:18]=1[O:39][CH3:40])[CH:14]=[CH2:15]
Reactant: CI
Reactant: C=CCOC(=O)C1CCN(C(=O)C=Cc2ccc(OCC=C)c(OC)c2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1(C)CCN(C(=O)C=Cc2ccc(OCC=C)c(OC)c2)CC1

Procedure:
50 ml of sodium hexamethyldisilazide (1M solution in THF) and 5.3 ml of methyl iodide were added to a solution of 7.8 g of allyl 1-(4-allyloxy-3-methoxycinnamoyl)-piperidine-4-carboxylate (Example 66) in 200 ml of THF. The solution was reacted for 18 hours at room temperature. After reaction, 200 ml of an aqueous ammonium chloride solution was added to the reaction solution. The solution was extracted three times with 100 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 100 g of silica gel. From the fraction eluted with hexane and ethyl acetate=3:2, the solvent was removed in vacuo, yielding 1.1 g of allyl 1-(4-allyloxy-3-methoxycinnamoyl)-4-methylpiperidine-4-carboxylate (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties: