Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[O:24][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=3)[O:24][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Oc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(COc2ccc(-n3nc(C)n(C(F)F)c3=O)c(F)c2)c1
Yield: 89.8 %

Procedure:
By the method of Example 1, Step K, 1.0 g (0.0038 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step F) and 1.72 g (0.0076 mole) of methyl 2-(3-chloromethylphenoxy)propionate were reacted in the presence of 0.79 g (0.0057 mole) of anhydrous potassium carbonate in 25 mL of N,N-dimethylformamide, yielding 1.54 g of methyl 2-[3-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]phenoxy]propionate. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 2.44 (s, 3H); 3.76 (s, 3H); 4.78 (q, 1H, JHH =8.0 Hz); 5.04 (s, 2H); 6.76-7.38 (m, 8H).
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:19]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[CH3:20].C(O)C>Cl.O>[CH2:19]([N:21]1[C:1]([C:2]2[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:13][C:14](=[O:16])[N:24]([CH2:25][CH3:26])[C:22]1=[O:23])[CH3:20]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: CCNC(=O)NCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=O)n(CC)c1=O
Temperature: 120 °C
Yield: 26.5 %

Procedure:
To a mixture of ethyl veratroylacetate (10 g) and N,N'-diethylurea (5.06 g) were added conc.hydrochloric acid (1 drop) and ethanol (1 ml). The mixture was heated at 120° C. for 3.5 hours under reduced pressure. To the residue was added another conc.hydrochloric acid (2 drops) and the mixture was heated again at 120° C. for 4 hours under reduced pressure. To the reaction mixture was added water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with a mixture of diisopropyl ether and ethyl acetate to give 1,3-diethyl-6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (3.20 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[OH-].[Na+].C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)(=[O:3])[CH:2]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 50.3 %

Procedure:
A solution of 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine (1.0 g), benzaldehyde (177 mg) and concentrated sodium hydroxide (3 drops) in ethanol (25 ml) was stirred at ambient temperature overnight to give a solid which was filtered, washed with ethanol and dried to give 1-(4-cinnamoylphenyl)-4-(4-pyridyl)piperazine (310 mg), m.p. 208-210° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16]1[C:20]2[C:21]([OH:29])=[C:22]([CH2:26][CH2:27][CH3:28])[CH:23]=[C:24]([Cl:25])[C:19]=2[O:18][CH:17]=1>C(Cl)CCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[O:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([CH2:26][CH2:27][CH3:28])=[C:21]([O:29][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=4)[C:20]=3[C:16]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCCc1cc(Cl)c2occ(C)c2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(Cl)c2oc(C(=O)c3ccc(Br)cc3)c(C)c2c1OC(=O)c1ccc(Br)cc1
Reaction time: 0.17 h

Procedure:
A solution of p-bromobenzoyl chloride (1.1 gm; 5.0 mmoles) in ethylene dichloride (5 mL) was added slowly to a cooled suspension of aluminium chloride (3.3 gm; 25 mmoles) in ethylene dichloride (75 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.95 gm; 4.2 mmoles) in dichloroethylene (20 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice-bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 260 mg gm of 2-(p-bromobenzoyl-3-methyl-4-(p-bromobenzoyloxy)-5-propyl-7-chlorobenzofuran.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]2[CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH2:9][N:8]2[C:20](=[O:35])[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:3]2[CH:36]=[CH:37][CH:38]=[CH:39][C:2]1=2.[Cl:40]C(OC(Cl)C)=O>ClCCl>[ClH:40].[S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]2[CH2:12][NH:11][CH2:10][CH2:9][N:8]2[C:20](=[O:35])[C:21]2[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=2)[C:3]2[CH:36]=[CH:37][CH:38]=[CH:39][C:2]1=2
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1csc2ccccc12
Solvent: ClCCl
Product: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R)-2-(benzo[b]thiophen-3-yl-methyl)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.75 g) in dichloromethane (8 ml) was added dropwise 1-chloroethyl chloroformate (0.19 ml) at ice-bath temperature. The resulting mixture was stirred at room temperature for 1 hour and then at reflux temperature for 5 hours. The reaction mixture was evaporated under reduced pressure. Methanol (5 ml) was added to the residue and the whole mixture was heated under refluxing for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between aqueous sodium bicarbonate solution (10 ml) and ethyl acetate (20 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was treated with 4N hydrogen chloride in ethyl acetate solution to afford (2R)-2-(benzo[b]thiophen-3-yl-methyl)-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine hydrochloride (0.69 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][C:6]1[S:27][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[N:12]([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:13](=[O:14])[C:8]=2[C:7]=1[CH:28]=[O:29].[Cl:33][C:34]1[CH:35]=[C:36]([Mg]Br)[CH:37]=[CH:38][CH:39]=1>C1COCC1.CC(=O)OCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][C:6]1[S:27][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[N:12]([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:13](=[O:14])[C:8]=2[C:7]=1[CH:28]([C:37]1[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][CH:38]=1)[OH:29]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Oc3cccc(Cl)c3)sc21
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
To a solution of 6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (65 mg, 0.136 mmol) in THF (2 mL) was added (3-chlorophenyl)magnesium bromide (35 mg, 0.163 mmol). The reaction was stirred at RT for 15 minutes then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by chromatography eluted with PE/EA (4:1) to give 6-(3-chlorophenoxy)-5-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (45 mg, 56.3% yield) as a yellow oil. LCMS: MH+ 591 and TR=2.138 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:31][CH:30]=3)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][O:44][CH2:45][CH2:46][O:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][CH:54]=1.[OH-].[NH3+]N.CCOCC>O.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[C:19]([C:56]3[CH:55]=[CH:54][C:53]([CH2:52][CH2:51][CH2:50][O:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH3:43])=[CH:58][CH:57]=3)[CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:31][CH:30]=3)[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Oc1cc(-c2ccc(OCc3ccccc3)cc2)cc(-c2ccc(OCc3ccccc3)cc2)c1)C(F)(F)F
Reactant: COCCOCOCCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: N[NH3+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COCCOCOCCCc1ccc(-c2cc(-c3ccc(OCc4ccccc4)cc3)cc(-c3ccc(OCc4ccccc4)cc3)c2)cc1

Procedure:
4.00 g (6.78 mmol) trifluoromethanesulfonic acid-4,4″-bis-benzyloxy-[1,1′;3′,1″]terphenyl-5′-yl ester, 2.37 g (6.78 mmol) 2-{4-[3-(2-methoxyethoxymethoxy)-propyl]-phenyl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 2.85 g (20 mmol) sodium metaborate-tetrahydrate are dissolved in 8 ml water and 20 ml THF. 97 mg (0.135 mmol) bis(triphenylphosphine)palladium(II)chlorid and 0.01 ml hydraziniumhydroxide are added and the mixture is heated at reflux for 5 h. MTB ether is added, the aqueous layer is separated and extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is filtered through silica gel with dichloromethane/MTB ether (95:5), to give 4,4″-bis-benzyloxy-5′-(4-[3-(2-methoxy-ethoxymethoxy)-propyl]-phenyl)-[1,1′;3′,1″]terphenyl as a brown oil which is reacted in the next step without further purification.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](#[N:30])[CH:28]=[CH2:29]>>[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][N:11]([CH2:29][CH2:28][C:27]#[N:30])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: C=CC#N
Agent: Cl
Solvent: CCN(CC)CC
Product: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a suspension of 4,4-diphenylpiperidine hydrochloride (195 mg, 0.712 mmol, 1.0 equiv) in ETOH (1.5 mL) was added triethylamine (0.25 mL, 1.83 mmol, 2.6 equiv) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 equiv). The resulting solution was stirred at room temperature under argon for 15 minutes and then concentrated. Water was added, and the mixture was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated to give 170 mg (87%) of tan solid, which was used for the next reaction without purification. mp 95°-96° C.; 1H NMR (300 MHz, CDCl3) δ 2.37 (m, 2H), 2,46 (m, 4H), 2.52 (m, 6H), 7.12 (m, 2H), 7.23 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 16.65, 36.71, 45.08, 50.78, 54.13, 119.70, 126.48, 127.78, 129.11, 147.87; IR (neat) 2944.4, 2821.0, 1495.5, 1445.9 cm-1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](C)[CH:14]=2)[CH2:10][CH2:11][CH3:12])[CH:5]=[N:4][CH:3]=1.[CH3:20]C1(C)C(C)(C)OB(C2C=CC(O)=CC=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)CC.C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH3:12])[CH:5]=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CCCC(Nc1cncc(Cl)n1)c1cccc(C)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: CCOC(C)=O
Solvent: CCCO
Solvent: Cc1ccccc1
Product: CCCC(Nc1cncc(Cl)n1)c1ccc(C)cc1

Procedure:
Under a nitrogen atmosphere a mixture of 6-chloro-N-[1-(3-methylphenyl)butyl]pyrazin-2-amine (0.21 g, 0.76 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.23 g, 91 mmol), tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) in toluene-n-propanol (4 mL, 3:1) was treated with 2M aqueous sodium carbonate solution (0.4 mL, 0.84 mmol). The resulting mixture was stirred vigorously whilst being heated under reflux for 22 hours. Once cool ethyl acetate was added and the mixture dried (MgSO4) and filtered. Removal of solvent in vacuo then yielded crude product, which was purified by column chromatography using dichloromethane:diethyl ether (90:10) as eluent to furnish (0.165 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[C-:17].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=O>Cl(O)(=O)(=O)=O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][NH:16][C:17]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]2=[N:1][C:28]=1[C:27]1[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: [C-]#[N+]CC(=O)OC
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CNc1c(-c2cc(OC)cc(OC)c2)nc2c(OCc3ccccc3)cccn12

Procedure:
Compound (9) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3-benzyloxypyridine solution (0.1 M, DCM), 0.575 ml of methyl isocyanoacetate solution (0.2 M, DCM), 0.500 ml of 3,5-dimethoxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[C:16]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: N#Cc1cccnc1F
Reactant: Oc1cccnc1Cl
Product: N#Cc1cccnc1Oc1cccnc1Cl

Procedure:
2-Fluoro-nicotinonitrile was reacted with 2-chloro-pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 232 (M)+, 234 (M+2)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](=[O:9])([O-])[OH:7].[Na+].[CH2:11](OCl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>O1CCOCC1.O>[CH2:11]([O:7][C:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])O
Reactant: ClOCc1ccccc1
Reactant: NCCCO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCCCO)OCc1ccccc1
Yield: 62 %

Procedure:
3-Amino-l-propanol (5.0 g) was dissolved in a mixture of dioxane (50 ml) and water (50 ml), and to the resulting solution were added under ice-cooling sodium hydrogen carbonate (4.3 mg) and benzyloxychloride (15.6 ml). The resultant mixture was stirred at that temperature for 1.5 hours. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so separated was dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the title compound (8.5 g; 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1>>[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]3)[CH:20]=[CH:24][CH:23]=[CH:22]1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F
Reactant: COC1CCC(OC)O1
Product: O=c1[nH]c2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O

Procedure:
12.2mmol of 6-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 12.2 mmol of 2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[O:15])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O>[C:29]([O:15][N:14]=[C:11]1[CH:12]=[CH:13][C:8](=[N:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:9]=[CH:10]1)(=[O:31])[CH3:30]
Reactant: O=Nc1ccc(Nc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)ON=C1C=CC(=Nc2ccccc2)C=C1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution was prepared by mixing 4-nitrosodiphenylamine, 19.8 grams, (0.10 mole), pyridine, 8.6 grams, (0.11 mole), and toluene, 10 mL, in a suitable reaction flask. The solution was cooled to 5° C. and acetic anhydride, 11.22 grams, (0.11 mole) was added slowly. The mixture was stirred for 2 hours and allowed to come to room temperature. The reaction mixture was mixed with a quantity of water, allowed to stand until the water layer separated, and the water layer was discarded. The toluene solution was evaporated to leave 21.4 grams of a solid residue, 96% of theory. The material melted at 63-65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[CH:27]([NH2:30])([CH3:29])[CH3:28]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:30][CH:27]([CH3:29])[CH3:28])[CH:9]=2
Reactant: CC(C)N
Reactant: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)c1
Solvent: CO
Product: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC(O)CNC(C)C)cc3o2)c1

Procedure:
3′,5′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 32 (700 mg, 2 mmol) and iso-propyl amine (1.0 mL, 12 mmol) in dry methanol (120 mL) were reacted in a similar manner to that described under 34 to afford 44. Yield 720 mg (87%); mp 155-156° C.; MS (FAB) 414 (M++1); IR (KBr) 3426, 1630; 1H NMR (200 MHz, DMSO-d6) δ 7.95 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 7.18 (d, J=1.8 Hz, 2H), 7.09 (dd, J=8.9 Hz, 1.9 Hz, 1H), 6.96 (s, 1H), 6.70 (s, 1H), 4.20-3.90 (m, 3H), 3.85 (s, 6H), 2.84-2.58 (m, 3H), 1.03 (d, J=6.2 Hz, 6H). Analysis Calcd for C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found: C, 66.69; H, 6.13; N, 3.62.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].C(Cl)(=O)C([Cl:9])=O.[NH:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>C(Cl)Cl>[Cl-:9].[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:4]=[N+:2]([CH3:3])[CH3:1]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1cc[nH]c1
Solvent: ClCCl
Product: C[N+](C)=Cc1ccc[nH]1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A solution of DMF (60.0 mL, 738 mmol) in DCM (60 mL) was added to a stirred solution of oxalyl chloride in DCM (60 mL) at 0° C. The mixture was stirred at 0° C. for 20 min then a solution of pyrrole (45.0 g, 666 mmol) in DCM (150 mL) was added over 15 min. This reaction mixture was stirred at rt for 20 min and concentrated to roughly half its volume. Petroleum ether (200 mL) was added and the precipitate was collected by filtration to give N-((1H-pyrrol-2-yl)methylene)-N-methylmethanaminium chloride (90.0 g, 80%). 1H NMR (DMSO-d6, 400 MHz) δ 13.23 (s, 1H), 8.65 (s, 1H), 7.79 (s, 1H), 7.45 (s, 1H), 6.68 (q, J=1.6 Hz, 1H), 3.70 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH:19]([CH3:39])[C:20]([O:22][CH2:23][CH2:24][O:25][C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)=[O:27])=[O:21].S(=O)(=O)(O)O>C(#N)C.COC(C)(C)C.O>[CH3:18][CH:19]([CH3:39])[C:20]([O:22][CH2:23][CH2:24][O:25][C:26]([NH:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:27])=[O:21].[CH3:38][S:35]([C:32]1[CH:33]=[CH:34][C:29]([OH:28])=[CH:30][CH:31]=1)(=[O:36])=[O:37]
Reactant: CC(C)C(=O)OCCOC(=O)Oc1ccc(S(C)(=O)=O)cc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CC(C)C(=O)OCCOC(=O)NCC1CCC(C(=O)O)CC1
Product: CS(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trans-4-(Aminomethyl)-cyclohexanecarboxylic acid (0.94 g) and water (25 mL) were charged to a vessel at room temperature. Potassium carbonate (0.8 g) was added in one portion and the mixture was stirred at room temperature for 5 minutes. A solution of [4-(methylsulfonyl)phenoxycarbonyloxy]ethyl 2-methylpropanoate D3 (1.6 g) in acetonitrile (25 mL) was added. After 6 hours, tert-butyl methyl ether (50 mL) was added and the reaction mixture was cooled to 5-10° C. A solution of 5% aqueous sulfuric acid was added to adjust the pH to approximately 3. The mixture was then warmed to room temperature and stirred for 10 minutes. The organic layer was washed with water (3×10 mL) and evaporated to yield the title compound as an orange oil with 4-(methylsulfonyl)phenol as an impurity. Tert-butyl methyl ether (10 mL) and methylcyclohexane (5 mL) were added and the mixture was heated at 50° C. for 10 minutes. The mixture was then cooled to 40° C. over a period of 2 hours. The crystallization solution was seeded with 4-({[(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)cyclohexanecarboxylic acid (10 mg) and then stirred for 2 hours. The white, thick slurry was filtered and dried under vacuum at room temperature to provide 1 g of the title compound E2.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[N:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[N:14]2[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]2=[N:16][N:17]=1
Reactant: O=C(NNc1ccc(F)cn1)c1ccccc1Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc2nnc(-c3ccccc3Cl)n2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
Hexachloroethane (3.47 g, 14.68 mmol) was added portionwise at RT to a stirred mixture of Intermediate 31a (1.95 g, 7.34 mmol), triphenylphosphine (3.85 g, 14.68 mmol), and triethylamine (4.12 mL, 29.36 mmol) in anhydrous THF (60 mL). The reaction mixture was stirred at RT for 3.5 h. The resulting suspension was filtered, washing the solid with Et2O. The filtrate was concentrated in vacuo and the resultant residue purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 2M NH3 in MeOH to give the title compound (1.81 g, quantitative) as a fawn coloured solid. LCMS (Method 3): Rt 2.96 min, m/z 248 [MH+].