Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[CH2:19][CH2:20][C:21]([O:23]C)=[O:22].Cl>[OH-].[Na+]>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]([OH:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:16])([F:17])[F:15])[CH:6]=[CH:5][C:4]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CCC(=O)O

Procedure:
To a solution of 3,4-dihydro-7-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2H-1-benzothiapyran-2-one in dimethylacetamide can be added a one molar excess of sodium hydroxide in methanol. The resulting solution should be heated, and a one molar excess of methyl iodide should be added with stirring. From the resulting reaction mixture can be isolated 2-methylthio-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester. This ester should be dissolved in an aqueous solution of sodium hydroxide to obtain a solution which will be heated on a steam bath. Concentrated hydrochloric acid can then be added to this solution, thereby yielding a precipitate which can be isolated to give 2-methylthio-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid.
Reaction SMILES: [C:1]12([C:11]3[S:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=O)C>>[C:1]12([C:11]3[S:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]([C:27](=[O:28])[CH2:26][CH2:25][SH:24])[N:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CCOC(=O)C1NN=C(C23CC4CC(CC(C4)C2)C3)S1
Product: CCOC(=O)C1SC(C23CC4CC(CC(C4)C2)C3)=NN1C(=O)CCS

Procedure:
The crude product of step (c) was treated with 3-acetylthiopropanoyl chloride by the process of Example 3, step (b) to give the sub-title product as an oil.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:2]2[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCc1ccccc1
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)c(NCCCc2ccccc2)cn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
500 mg of dimethyl 5-bromo-pyridine-2,4-dicarboxylate (from Example 3) are dissolved in 10 ml of toluene. 0.26 ml of phenylpropylamine are added dropwise and the mixture is stirred at 120° C. for 10 hours. After cooling, the solvent is evaporated off, the residue is taken up in ethyl acetate and the organic phase is washed with 2 portions each of citric acid, sodium bicarbonate solution and water. After drying over magnesium sulfate, the solvent is evaporated. Chromatography on silica gel gives 117 mg of product with a melting point of 102°-104° C.
Reaction SMILES: O[CH:2]1[CH2:7][O:6][CH:5]([C:8]([O:10]CC)=[O:9])[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:2]12[CH2:3][CH2:4][CH:5]([O:6][CH2:7]1)[C:8](=[O:9])[O:10]2
Reactant: CCOC(=O)C1CCC(O)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OC2CCC1OC2
Temperature: 25 °C

Procedure:
A mixture of the cis and trans isomers of ethyl 5-hydroxytetrahydropyran-2-carboxylate (3.9 g, 0.023 mol) was dissolved in dry toluene (200 ml). p-Toluene-sulfonic acid monohydrate (0.20 g, 1.1 mmol) was added as a catalyst. The mixture was refluxed for 7 hours through a Soxhlet extractor containing molecular Type A sieves in a thimble. The mixture was cooled to room temperature, and anhydrous sodium carbonate (5 g) was added to neutralize the acid. The solution was passed through a short pad of silica gel and concentrated. A brown viscous oil was subjected to column chromatography (column, silica gel; eluent, n-hexane/ethyl acetate, 1:1 v/v). The crude product thus isolated was purified by repeated recrystallization from a mixture of ethyl ether and n-hexane (5-20:1 v/v). The lactone has a melting point of 56°-57° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30]([N:32]1[CH2:35][C:34]2([CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:37]3[CH2:38][CH2:39][C:34]4([CH2:35][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])[CH2:33]4)[CH2:36]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNC2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)C2)C1
Temperature: -60 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.3 g, 1 eq.) dissolved in ethylacetate (20 mL) and cooled to −70° C. where tert-butyl-2,6-diazaspiro[3.4]octane-2-carboxylate (0.22 g, 1.2 eq.), T3P (50% in EtOAc) (0.61 mL, 1.2 eq.), followed by DIPEA (0.6 mL, 4 eq) were added. The clear reaction mixture was stirred at −60° C. for 1 h, concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (3-4% Methanol in DCM) to yield (Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (0.2 g; 43% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1c(F)cccc1F

Procedure:
To a suspension of 2,6-difluorobenzaldehyde (374.7 mg, 2.64 mmol), 1,1-dimethylnitroethane (541.6 mg, 5.25 mmol) and zinc (517.0 mg, 7.91 mmol) in ethanol (3.0 ml) was added acetic acid (940.5 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=5/2-2/1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: C1CCNCC1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCCCC2)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and piperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.28 (d, 1H), 8.22 (m, 1H), 7.88 (m, 1H), 7.59 (m, 2 H), 7.42 (d, 1H), 7.40 (s, 1H), 7.15 (m, 1H), 7.05 (d, 1H), 4.35 (broad t, 2H), 3.61 (m, 4H), 3.38 (s, 4H), 2.90 (broad t, 2H), 2.60 (m, 4H), 1.60 (m, 6H). MS: 461.4 (M+1).
Reaction SMILES: [CH3:1]/[C:2](=[CH:10]\[CH2:11][CH2:12]/[C:13](/[CH3:23])=[CH:14]/[CH2:15][O:16]C1CCCCO1)/[CH2:3][CH2:4][CH:5]([OH:9])[CH2:6][C:7]#[CH:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH3:23]/[C:13](/[CH2:12][CH2:11]/[CH:10]=[C:2](\[CH3:1])/[CH2:3][CH2:4][CH:5]([OH:9])[CH2:6][C:7]#[CH:8])=[CH:14]\[CH2:15][OH:16]
Reactant: C#CCC(O)CC/C(C)=C/CC/C(C)=C/COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C#CCC(O)CC/C(C)=C/CC/C(C)=C/CO

Procedure:
A solution of 6.40 g of (E,E)-7,11-dimethyl-13-[(tetrahydro-2H-pyran-2-yl)oxy]-7,11-tridecadien-1-yn-4-ol and 1.50 g of pyridinium toluene-4-sulfonate in 200 ml of abs. ethanol is heated to 60° under argon for 2.5 hours. The reaction mixture is cooled and evaporated, and the residue is taken up in ether and water. After separating the organic phase the aqueous phase is extracted twice with ether and the combined organic phases are washed with 2N hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The yellow oil which remains behind as the residue is chromatographed on 400 g of silica gel, with elution being carried with hexane-ethyl acetate 25%→40%. In this manner there is obtained (E,E)-3,7-dimethyltrideca-2,6-dien-12-yn-1,10-diol as a yellowish oil. IR (film); 3350 (OH); 3305, 2118 (--C≡CH); 1667 (C=C); 1003, (OH). MS: 205 (1, (M--CH 2 OH)+); 203 (1, M--H2O--CH3)+); 105 (100); 93 (100).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[C:13]([C:14]4[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=4)=[C:9]3[C:8](=[O:34])[N:7]([CH3:35])[C:6]2=[O:36])[CH2:3][CH2:2]1.Cl.[O:38]([NH2:40])[CH3:39].C(P(=O)(OCC)OCC)#N>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[C:13]([C:14]4[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([NH:40][O:38][CH3:39])=[O:22])[CH:15]=4)=[C:9]3[C:8](=[O:34])[N:7]([CH3:35])[C:6]2=[O:36])[CH2:3][CH2:2]1
Reactant: CON
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC3CC3)c2c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(C)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{7-(cyclopropylmethyl)-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent. Mass: 516.21 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:15](N(CC)CC)C>O1CCOCC1>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccnc1Cl
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1Cl
Yield: 85.4 %

Procedure:
To a mixture of 2-chloronicotinic acid (Aldrich, 100.0 g, 0.63 mol) in 1,4-dioxane (500 mL) was added thionyl chloride (70 mL, 0.96 mol). The suspension was heated under reflux for 22 h with a gas trap to absorb hydrogen chloride gas. After evaporation of the solvent, the residue was dissolved in methanol (300 mL). To the solution was added dropwise triethylamine (TEA, 120 mL, 1.26 mol) at 0° C. over 2 h. The solvents were evaporated and the residue was suspended in ethyl acetate. The precipitate was removed by filtration. The filtrate was concentrated to afford the ester 18 (92.3 g, 86%) as an oil:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([O:26]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(O)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (4.21 g, 8 mmol) and 5% palladium carbon (2.0 g) in ethanol (20 ml) and tetrahydrofuran (20 ml) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-hydroxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.28 g, 94.0%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:33]=3[N:24]=[CH:25][CH:26]=[CH:27]4)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4cccnc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with quinoline-8-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=488.2.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].C([N:26]1C2C(=CC=C([N+]([O-])=O)C=2)C(C2C=CC(C#N)=CC=2)=C1)(C)C.S(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:26][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[C:10]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)=[CH:11]1
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Agent: O=S([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cn(N)c3cc([N+](=O)[O-])ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add NaH (98 mg, 2.47 mmol) to 4-(6-nitro-1H-indol-3-yl)-benzonitrile (500 mg, 1.9 mmol) in DMF (10 mL) at 0° C. under N2 and stir for additional 30 min at room temperature. Add excess NH2Cl ether solution prepared according to the procedure described in J. Org. Chem. 2004, 69 (4), 1369, and stir for an hour. Add 10% sodium bisulfite and extract with EtOAc. Wash the EtOAc extracts with 10% sodium bisulfite twice and dry over MgSO4. Evaporate the solvent to give 4-(1-amino-6-nitro-1H-indol-3-yl)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1ccc(N)cc1
Product: COC(=O)C(=O)Nc1ccc(C)cc1

Procedure:
The method described in Referential Example 242 was performed by use of p-toluidine and methyl chlorooxoacetate, whereby the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([F:20])=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[N:26]=[CH:25]1.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[CH:10][C:11]([F:20])=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:13]=2)[S:29]([C:27]2[N:26]=[CH:25][N:24]([CH3:23])[CH:28]=2)(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: O=C1CCCN1c1cc(NCc2ccc(Cl)cc2)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2ccc(F)c(N3CCCC3=O)c2)c1
Yield: 42.1 %

Procedure:
1-[5-(4-Chloro-benzylamino)-2-fluoro-phenyl]-pyrrolidin-2-one (32 mg, 0.1 mmol), 1-methylimidazole-4-sulfonyl chloride (54 mg, 0.3 mmol) and pyridine (24 ul, 0.3 mmol) were refluxed in dry dichloromethane (3 ml) for 18 hrs. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to afford the title compound as a yellow oil (19.5 mg, 42%). HPLC retention time 4.3 min, Mass spectrum (ES+) m/z 464 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][CH2:10][C:11](Br)=[O:12].C(N(CC)CC)C>ClCCl>[Br:9][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Nc1ccc(I)cc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 4-iodoaniline (14.5 mmol) in anhydrous dichloromethane at 0° C. was added a-bromo-acetylbromide (1.4 mL) and triethylamine (15 mmol). The mixture was warmed to room temperature, stirred for 1 h, the solvent removed, and residue dissolved in 5% hydrochloric acid. The aqueous solution was extracted with ethyl acetate, the organic layer washed with brine, dried (Na2SO4), filtered, and evaporated. The solid residue was purified by recrystallization form ethyl acetate to afford the desired intermediate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N2CCN(CC2)C1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][S:30]([C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)(=[O:31])=[O:32])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a stirred solution of 4-nitrobenzeneethanol (3.34 g, 20.0 mmol) and triethylenediamine (3.36 g, 30.0 mmol) in DCM (62.7 mL) at 0° C. was added 4-nitrobenzenesulfonyl chloride (4.97 g, 22.43 mmol) in portions over a 5 min period. The reaction mixture was then stirred at room temperature for 2 h. Water (50 mL) was added and the resulting mixture was stirred for 10 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (5.8 g, 82% yield) as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:29]1[C:30]([CH3:38])=[CH:31][C:32]2[N:33]([N:35]=[CH:36][N:37]=2)[N:34]=1>O1CCCC1>[C:22]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:29]3[C:30]([CH3:38])=[CH:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[N:34]=3)[CH2:14][CH2:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1cc2ncnn2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
260 mg of 60% sodium hydride dispersion in mineral oil was suspended in 20 ml of tetrahydrofuran; 1.15 g of 2-[2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy]ethanol was added, followed by heating and refluxing for 1 hour. After cooling, 540 mg of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 3 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (10:10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 730 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[N+:25]([O-:27])=[O:26]>CN(C=O)C.O>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:20]2[CH:21]=[CH:16][C:17]([N+:25]([O-:27])=[O:26])=[CH:18][C:19]=2[N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1
Reactant: NCc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(CNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-aminobenzylamine (25.5 mL, 225 mmol) and powdered NaHCO3 (94.5 g, 1125 mmol) in anhydrous DMF (300 mL) was added 2,4-dinitrofluorbenzene (1) (18.8 mL, 150 mmol) dropwise at room temperature. After 2 hours, the solution was slowly diluted with water (1000 mL) to precipitate the product, which was collected on a fritted funnel while rinsing with water until the eluent was colorless. The solid was further dried under high vacuum to afford 43.0 g as a bright orange solid in 99% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5](C)=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O[CH:20](C1OC=CC(=O)C=1O)C.C(Br)C1C=CC=CC=1>>[OH:1][CH:2]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:20]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Reactant: CC(O)c1occc(=O)c1O
Agent: BrCc1ccccc1
Product: CC(O)c1occc(=O)c1OCc1ccccc1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 4.68 g (30 mmol, 1 eq.) of 2-(1-hydroxyethyl)-3-hydroxy-pyran-4(1H)-one and 5.64 g benzyl bromide (33 mmol, 1.1 eq.) to yield the pure product 6.1 g (82%) after recrystallisation from CH2Cl2/Pet. ether 40/60, as a white crystalline solid. m.p. 97-100° C.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH2:13]([OH:16])[C:14]#[CH:15]>C(OCC)C>[OH:16][CH2:13][C:14]1[CH:15]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: CCOCC
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2.0 g (0.0126 mole) of 3-diazooxindole is dissolved in 22 ml of propargyl alcohol (0.378 mole) and refluxed under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and diluted with 10 volumes of ethyl ether. The solid is filtered, washed with ethyl ether and dried to give 2.0 of product (75% direct yield). Recrystallization from methanol gives 1.5 g of title compound, m.p. 286°-288° (sl. dec.).