Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=O)[CH:7]=[N:8][CH:9]=1.[OH:12][C:13]([CH3:18])([CH3:17])[C:14](=[O:16])[CH3:15]>CO.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:15]/[C:14](=[O:16])[C:13]([OH:12])([CH3:18])[CH3:17])[CH:7]=[N:8][CH:9]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CC(=O)C(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(O)C(=O)/C=C/c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (1.1 eq, 29.6 mmol, 29.6 ml) in MeOH (100 ml) under an inert atmosphere of nitrogen is cooled at 0° C. and treated with 5-bromo-pyridine-3-carbaldehyde (1 eq, 26.9 mmol, 5 g). After 1 h at 0° C., 3-hydroxy-3-methyl-butan-2-one (1 eq, 26.9 mmol, 2.75 g) is added and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is dissolved in EtOAc and washed with water. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (0-50% EtOAc in iso-hexane) to afford the title compound; [M+H]+ 270/272.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:18]([CH3:19])=[C:17]2[N:8]([C:9](=[O:20])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=[O:5])C>[OH-].[K+]>[CH3:19][C:18]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][N:8]2[C:17]=1[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:10][C:9]2=[O:20]
Reactant: CCOC(=O)c1nn2c(=O)[nH]c3ccccc3c2c1C
Agent: [K+]
Agent: [OH-]
Product: Cc1c(C(=O)O)nn2c(=O)[nH]c3ccccc3c12
Temperature: 25 °C

Procedure:
A suspension of 25.7 g (0.10 mole) of 1-methyl-pyrazolo[1,5-c]quinazolin-5(6H)-one-2-carboxylic acid ethyl ester in 2.5 l of 10% alcoholic potassium hydroxide is refluxed for 3 hours, cooled to room temperature and filtered. The solid is dissolved in water extracted with chloroform, treated with Norit-A and filtered. The filtrate is cooled in an ice bath and acidified (Congo red) with 25 ml of concentrated hydrochloric acid. The white precipitate is filtered, digested with 1 l. of hot water and filtered, and dried to give the title compound.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:8])C(OCC)=O.[C:10]1([S:16][CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+].CCOCC>O>[C:10]1([S:16][CH:17]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:2]2([Cl:8])[Cl:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Reactant: COC(=O)C=CSc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1C(Sc2ccccc2)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Freshly distilled ethyl trichloroacetate (164.8 g, 0.86 mmol) is added all at once to a cold (-50° ) stirred mixture of dry methyl 3-phenylthio-2-propenoate (155.4 g, 0.8 mol), dry olefin-free pentane (600 ml) and sodium methoxide (50 g, 0.92 mol). The cold mixture is allowed to stir under nitrogen at -50° for 4 hr and is then warmed slowly to RT over a period of 24 hr. Ether and water are added, and the organic layer is separated, washed with water, dried over calcium sulfate and solvent is removed under vacuum. The residue is purified by chromatography on silica gel, giving methyl 3-phenylthio-2,2-dichlorocyclopropanecarboxylate.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].N12CCCN=C1CCCCC2>C(#N)C>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(CS)c1
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CCSCc1cccc(C(=O)O)c1
Yield: 28 %

Procedure:
To a solution of 3-(mercaptomethyl)benzoic acid (500 mg, 2.97 mmol, 1.00 equiv) in acetonitrile (10.0 mL) was added methyl acrylate (10.0 mL) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.0 g, 6.57 mmol, 2.00 equiv) and the resulting solution was heated to reflux overnight. The reaction was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:6) to afford 220 mg (28%) of 3-((3-methoxy-3-oxopropylthio)methyl)benzoic acid as light-red oil.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1>ClCCl.O>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[CH2:2][N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: OC1CCNC1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CN1CCC(O)C1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and 3-pyrrolidinol (1.33 g, 15.2 mmol) in 10 mL dichloromethane were added, and the reaction was stirred at RT overnight. The reaction mixture was diluted with 100 mL of water, the organic solvents were washed with water (2×100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The resulting residue was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, and the reaction was stirred at RT overnight under a balloon of H2 pressure. The catalyst was removed via filtration and the solvent was evaporated under reduced pressure to yield the 1-{2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-pyrrolidinol as a white solid (3.0 g, 92%).1H NMR (400 MHz, DMSO-d6) δ ppm: 1.60 (m, 1 H), 1.97 (m, 1 H), 2.47(s, 1H), 2.59 (m, 1 H), 2.72 (m, 1 H), 2.85 (m, 1 H), 2.96 (m, 4 H), 3.50(s, 2H), 3.68(s, 3H), 4.00 (t, J=8.33 Hz, 2 H), 4.86 (s, 2H), 6.68 (s, 1 H), 7.51 (s, 1 H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:11][C:10]2[C:9](=O)[NH:8][CH:7]=[N:6][C:5]=2[CH:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[C:10]2[S:11][C:3]([S:2][CH3:1])=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1cc2nc[nH]c(=O)c2s1
Product: CSc1cc2ncnc(Cl)c2s1
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A mixture of 6-(methylthio)thieno[3,2-d]pyrimidin-4(3H)-one (900 mg) and phosphorous oxychloride (10 mL) was refluxed for 3 h. The reaction mixture was attained to rt and poured into ice cold water and stirred for 10 min. The precipitated solid was filtered, washed with water and dried to give the product as an off-white color solid (800 mg, 81%), mp 138-140° C. 1H NMR (400 MHz, CDCl3): δ 8.87 (1H, s), 7.25 (1H, s), 2.72 (3H, s).
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][CH3:28])[C:21](=[O:29])[CH2:20]2)=[C:16]([F:18])[CH:17]=1)=[O:10])C1C=CC=CC=1.C([Li])CCC.[CH2:35](OC(=O)CCC)[C@@H:36]1[O:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C1COCC1.CN1CCCN(C)C1=O>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:35][C@H:36]([CH2:37][OH:38])[O:8][C:9]2=[O:10])[CH:13]=[CH:14][C:15]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][CH3:28])[C:21](=[O:29])[CH2:20]1
Reactant: COCCN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COCCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
5-Benzyloxycarbonylamino-2-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)fluorobenzene (3.2 g) was dissolved in dry THF (100 ml) under argon, cooled to -78° C., and treated with a solution of n-butyllithium (1.6 M in hexane, 5.5 ml), keeping the temperature below -60° C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU, 10 ml) was added to the resulting mixture to facilitate stirring and (R)-glycidylbutyrate (0.93 ml) was added. The mixture was stirred at -78° C. for 30 minutes, before allowing the temperature to rise to ambient over 16 hours. Sodium bicarbonate solution (50 ml) was added, and the whole evaporated to dryness. Organic materials were dissolved from the residue using dichloromethane, and purified by chromatography on silica using as eluant a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (1.14 g).
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:15]([O:18][C:19]1[CH:28]=[C:27]([CH:29](O)CS(C)(=O)=O)[CH:26]=[C:25]([O:36][CH2:37][CH:38]=[CH2:39])[C:20]=1[NH:21][C:22](=[O:24])[CH3:23])[CH:16]=[CH2:17]>CS(C)=O>[CH2:15]([O:18][C:19]1[CH:28]=[C:27]([CH2:29][C:12]([C:13]#[N:14])=[CH:11][NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:26]=[C:25]([O:36][CH2:37][CH:38]=[CH2:39])[C:20]=1[NH:21][C:22](=[O:24])[CH3:23])[CH:16]=[CH2:17]
Reactant: C=CCOc1cc(C(O)CS(C)(=O)=O)cc(OCC=C)c1NC(C)=O
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCOc1cc(CC(C#N)=CNc2ccccc2)cc(OCC=C)c1NC(C)=O
Reaction time: 3 h

Procedure:
A mixture of 1.4 g. of sodium methylate, 3.75 g. of β-anilino-propionitrile and 6.3 g. of 2',6'-bis(allyloxy)-4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-acetanilide in 43 ml. of absolute dimethylsulfoxide was stirred at room temperature under an atmosphere of nitrogen and the exclusion of moisture for 3 hours, poured into 200 ml. of water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and evaporated. After chromatography on aluminum oxide and recrystallization from ethanol, there was obtained 2',6'-bis-(allyloxy)-4'-(3-anilino-2-cyano-allyl)-acetanilide having a melting point of 176°-178° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][C:6]1=[O:13])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2([OH:13])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH2:10][CH:5]2[CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])=[CH:20][CH:19]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCOC(OCC)C1CC(C)(C)CCC1=O
Product: CCOC(OCC)C1CC(C)(C)CCC1(O)c1ccc(Cl)cc1

Procedure:
reacting the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol and isolating or not isolating the 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol;
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:14]>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:14])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 26.1 gm (0.1 mole) 3,5-dichloro-2-hydroxybenzenesulfonyl chloride in 400 ml dry tetrahydrofuran was cooled to 0° with an ice bath, and 11 ml (0.5 mole) anhydrous ammonia was added dropwise, with stirring. The rate of addition was sufficiently slow so as to keep the temperature of the reaction medium less than 10°. The mixture was stirred for 1.5 hours at 0° then slowly warmed to room temperature. The solvent was removed in vacuo and the residue was treated with 100 ml H2O. A small amount of insoluble by-product was filtered off and then the aqueous solution was acidified to pH=2.0 with 1 N HCl solution. Filtration of the resulting white precipitate and drying of the precipitate at 50° under vacuum gave 23.6 gm (97%) white solid, m.p. >225°. The infrared spectrum showed strong absorption at 3300, 1540, 1450 and 1320 cm-1, and the nuclear magnetic resonance spectrum showed a broad singlet at 7.2δ, 3 protons, and a doublet of doublets at 7.8δ, 2 protons. These data are consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][N:11]3[C:15](=[O:19])[N:16]([CH3:18])[N:17]=[C:10]3[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[N:11]3[C:15](=[O:19])[N:16]([CH3:18])[N:17]=[C:10]3[C:9]=2[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)c(=O)[nH]n2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)c(=O)n(Cc3ccc(C#N)cc3)n2c1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
The solution of 7-(4-chlorophenyl)-2-methyl-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione (10 mg, 0.028 mmol), 4-(bromomethyl)benzonitrile (7 mg, 0.036 mmol), K2CO3(12 mg, 0.084 mmol) in DMF (0.5 ml), was heated at 80° C. for 20 min. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 4-((7-(4-chlorophenyl)-2-methyl-3,6-dioxo-8-(pyridin-4-yl)-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-5(6H)-yl)methyl)benzonitrile (6.5 mg, 40%) as the mono trifluoro acetate salt as a yellow solid. Rt=2.78, M+H=469; 1H NMR (CD3OD) δ 8.81(2H), 7.71-7.60(6H), 7.32(2H), 7.07(2H), 5.96(2H), 3.57(3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:21]=[C:20]([O:28][CH:29]([F:31])[F:30])[N:19]=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:17][C:18]1[N:19]=[C:20]([O:28][CH:29]([F:30])[F:31])[CH:21]=[C:22]([O:24][CH:25]([F:27])[F:26])[N:23]=1)=[O:16])(=[O:12])=[O:13])=[O:4]
Reactant: Nc1nc(OC(F)F)cc(OC(F)F)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC(F)F)cc(OC(F)F)n1

Procedure:
3.62 g (0.0158 mole) of 2-methoxycarbonylphenylsulfonylisocyanate and 2.63 g (0.0116 mole) of 2-amino-4,6-bis-(difluoromethoxy)pyrimidine are reacted in 50 ml of dioxan as described in Example 1, affording the title compound with a melting point of 186°-188° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=1.O.[NH2:21][NH2:22]>C(O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(N2CCCC2=O)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(N3CCCC3=O)cc2)=NN1

Procedure:
10.4 g (0.04 mole) of 4-(4-(2-oxo-pyrrolidin-1-yl)-phenyl)-4-oxo-butyric acid and 2 g (0.04 mole) of hydrazine hydrate are stirred under reflux in 100 ml of ethanol for 1 hour, the mixture is cooled and the product is filtered off with suction. The solid which has precipitated is stirred with sodium bicarbonate solution, filtered off with suction, washed and dried.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][CH:18]=1>C(O)C>[CH:23](/[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[CH:22][CH:21]=1)=[CH:24]/[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCC/C=C\c1ccc(OCCBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC/C=C\c1ccc(OCCC(C(=O)OCC)C(=O)OCC)cc1
Yield: 125.6 %

Procedure:
A solution of sodium (0.408 g, 17.7 mmol) in ethanol (50 ml) under nitrogen was treated with diethyl malonate, (2.84 g, 17.7 mmol) followed by 1-bromo-2-(4-[(Z)1-undecenyl]phenoxy)ethane, (1.30 g, 3.68 mmol). The solution was refluxed 30 h, then cooled and evaporated in vacuo to dryness. The residue was partitioned between ethyl acetate and water and the organic phase separated, washed with water, and dried, (MgSO4). Evaporation in vacuo gave 2.0 g of a yellow oil which was purified by column chromatography using silica gel, eluting with dichloromethane: n-hexane, [2:3] to yield 510 mg (32%) of the title compound as a colourless oil. νmax (film) 1510, 1570 (weak) 1608, 1735, 1753 cm-1 δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.25 (3H, t, J 7 Hz ester CH3), 1.25 (14H, m, (CH2 )7), 2.31 (4H, m, OCH2CH2, allylic CH2), 3.63 (1H, t, J 7 Hz, CH(CO2Et)2), 4.01 (2H, t, J 7 Hz, OCH2), 4.18 (4H, q, J 7 Hz, ester CH2), 5.54 (1H, d.t, Jd 12 Hz, Jt 7 Hz, =CH--alkyl), 6.31 (1H, d, J 12 Hz, ArCH=), 7.02 (4H, ABq, Δν 34 Hz, J 9 Hz, C6H4).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:20][C:5]1[CH:4]=[C:3]([Cl:21])[C:2]([NH:1][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][C:6]=1[C:8]1[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)Cl
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2Cl)c1=O
Product: CCOC(=O)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of 0.35 g of 3-(5-amino-2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-334) and 3.1 ml of ethyl chloroformate was stirred at 100° C. for 2 hours. After completion of the reaction, the reaction mixture was left cooling to room temperature, and the excess ethyl chloroformate was distilled out under reduced pressure. The residue was recrystallized from hexane, which afforded 0.32 g (yield, 79%) of 3-(2,4-dichloro-5-ethoxycarbonylaminophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-346; m.p., 116.2-C).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:33]([O-])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].B(F)(F)F>ClCCl>[P:33]([O:11][C@@H:10]1[O:12][C@@H:13]([CH3:32])[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:34]
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](OP(=O)(OCc2ccccc2)OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 2,3,4-tri-O-benzyl-L-fucopyranose (prepared, for example, according to Wegmann et al., supra.) (0.50 g, 0.86 mmol) in 20 ml of dry dichloromethane and commercially available dibenzyl phosphate which is not further purified (0.24 g, 0.86 mmol) is stirred under a nitrogen atmosphere at room temperature for about 2 h. In the case of very pure dibenzyl phosphate, a catalytic amount of boron trifluoride is added to the mixture. The solution is then concentrated and purified by chromatography (toluene/acetone 9:1). Dibenzyl 2,3,4-tri-O-benzyl-α-L-fucopyranosyl phosphate (4) is obtained in a yield of 90% as a colorless oil (0.54 g). TLC (toluene/acetone 7:1) gives an Rf of 0.60, [α]578 =-68.2 (c=1, chloroform).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:23][S:24]([CH2:27][CH2:28]O)(=[O:26])=[O:25]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: CS(=O)(=O)CCO
Product: CS(=O)(=O)CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIq was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(methylsulfonyl)ethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[ClH:7]>>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3]1[N:4]=[C:3]([C:2]([Cl:1])([Cl:7])[Cl:7])[N:4]=[C:3]([C:2]([Cl:6])([Cl:5])[Cl:1])[N:4]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: Cl
Product: ClC(Cl)(Cl)c1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Aluminum bromide (0.5 g, 0.0019 mol) was added to a solution of the compound 5a (4.4 g, 0.019 mol) obtained in the above (1) dissolved in trichloroacetonitrile (43 g, 0.298 mol). Dry hydrogen chloride gas was passed through the reaction mixture at −10° C. for 2 hours. Then, the mixture was stirred at room temperature for one day. Trichloroacetonitrile was removed under reduced pressure. The residue was purified by a column (hexane/ethyl acetate=9/1). As a result, the mixture of 2,4-trichloromethyl-(2′-acetylbiphenyl)-6-triazine (5b) and 2,4,6-tris(trichloromethyl)-1,3,5-triazine was obtained. These two products were not separated since they have similar solubility in any solvent.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].[Cl:22][C:23]1[N:32]=[C:31](Cl)[C:30]2[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:34][CH3:35])[CH:29]=2)[N:24]=1>>[Cl:22][C:23]1[N:32]=[C:31]([N:18]2[CH2:19][CH2:20][CH:15]([N:5]3[C:6](=[O:14])[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=4)[N:3]([CH3:2])[C:4]3=[O:21])[CH2:16][CH2:17]2)[C:30]2[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:34][CH3:35])[CH:29]=2)[N:24]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1cc2nc(Cl)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 48 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 2,4-dichloro-6,7-dimethoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 239.2 mg (yield: 48%) of Compound 78 was obtained as white crystals.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>C(C(C)=O)C(C)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:11][CH:12]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(=O)OCc1ccc(O)cc1
Solvent: CC(=O)CC(C)C
Product: C=CC(=O)OCc1ccc(O[Si](C)(C)C)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1500 g of methyl isobutyl ketone and 100 g of 4-hydroxybenzyl acrylate were charged into a separable flask of the same type as used in Reference Example 3, and cooled to -5° C. while replacing the flask inside gas with a nitrogen gas, and then 67 g of trimethylchlorosilane was dropwise added thereto over one hour, and then stirring was continued for 2 hours. After completion of the reaction, the reaction mixture was washed with water and methyl isobutyl ketone was distilled off, whereby 83 g of p-trimethylsilyloxybenzyl acrylate of the following chemical formula was obtained (yield: 59%): ##STR3##