Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Na+].[CH:3](=[C:6]([C:11]([CH2:13]Cl)=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH3:5]>CN(C)C=O>[CH:3](=[C:6]([C:11]([CH2:13][Br:1])=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH3:5]
Reactant: CCC=C(C(=O)CCl)C(=O)OC
Reactant: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC=C(C(=O)CBr)C(=O)OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
In 10.23 g of N,N-dimethylformamide was dissolved 11.45 g of the concentrated solution (pure weight of methyl 2-propylidene-4-chloroacetoacetate: 4.57 g), and cooled to 10° C. To this mixture was added 6.17 g of sodium bromide, and thereafter heated to 22° C. and vigorously stirred at 22±2° C. for 2 hours. The resulting reaction solution was cooled to 5° C. and washed with 20 g of water, followed by being separated into an aqueous and organic layers. The high-performance liquid chromatography analysis of the organic layer indicated that this layer contained 4.66 g of methyl 2-propylidene-4-bromoacetoacetate (82.6% yield, E/Z ratio=52/48) and 9.7% of the starting material methyl 2-propylidene-4-chloroacetoacetate remained.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:45])[NH:12][C:13]2[CH:14]=[C:15]([CH:42]=[CH:43][CH:44]=2)[O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:40][CH3:41])=[C:24]([O:27][C@H:28]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:46].O1CCOCC1>>[ClH:46].[ClH:46].[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:12][C:13]2[CH:44]=[CH:43][CH:42]=[C:15]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:40][CH3:41])=[C:24]([O:27][C@H:28]5[CH2:32][CH2:31][NH:30][CH2:29]5)[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:14]=2)=[O:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of (S)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazole-3-yl)ureido)phenoxy)-7-methoxyquinazolin-6-yloxy)pyrrolidine-1-carboxylate (300 mg, ˜0.40 mmol), a 4N solution of HCl in dioxane (1 ml, 4 mmol) was added. The reaction mixture was stirred at room temperature overnight. The resulting solid was filtered and washed with plenty of ethyl ether to yield (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)urea dihydrochloride (215 mg, 91%). LC-MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Reactant: NCc1ccccc1
Product: N#Cc1c(NCc2ccccc2)cccc1-c1ccccc1
Temperature: 150 °C

Procedure:
The product of example 1a above, 2-fluoro-6-phenylbenzonitrile, (0.118 g, 0.6 mmol), and benzylamine (0.5 mL) were combined in a sealed tube that had been flushed with argon. The tube was heated in an oil bath to 150° C. for 24 hours. The residue was dissolved in methylene chloride (10 mL) and treated with an excess of polystyrene supported isocyanate resin for 30 minutes to remove the excess benzylamine. Filtration and evaporation gave the title product. ES (+) MS m/e=285 (MH+)
Reaction SMILES: [CH2:1]([C:4]1([CH:19]=[CH:20][O:21]C2CCCCO2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([C:4]1([CH2:19][CH:20]=[O:21])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(C=COC2CCCCO2)c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(CC=O)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Dissolved 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl-(2-tetrahydropyranyloxy-ethene) (4.82 g, 13.37 mmol) in 50 mL of THF. Added 50 mL of 0.2N HCl, and refluxed for 18 hours. Cooled to room temperature, and added 150 mL of saturated NaHCO3. Extracted with ethyl acetate. Washed combined organic extracts with saturated NaCl, dried (MgSO4), filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 10% ethyl acetate-hexane, Combined appropriate fractions and evaporated to give 3.32 g (90% yield) of 2-[10,11 -dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethanal). ##STR28##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>C(Cl)Cl.CCOC(C)=O>[C:44]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1/[CH:16]=[CH:15]/[C:13]1[CH:12]=[CH:11][C:10]([N:23]2[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:25](=[O:36])[CH2:24]2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=1)(=[O:46])[CH3:45]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CCCCC1/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Reaction time: 18 h

Procedure:
To a solution of 5-[2-benzyloxy-4-((E)-2-piperidin-2-yl-vinyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (101 mg, 0.192 mmol) in methylene chloride (4 mL) is added triethylamine (0.134 mL, 0.956 mmol). The solution is stirred at RT for 5 min the acetyl chloride (0.0163 mL, 0.23 mmol) is added and stirring is continued for 18 h. The mixture is diluted with EtOAc and is washed with 1N HCl and brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]([CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[N:13]=1)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[S:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][N:8]([C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)[N:13]=1)[CH2:7][C:6]([OH:29])=[O:5]
Reactant: CC(C)c1ccc(-c2csc(N(CC(=O)OC(C)(C)C)Cc3cccs3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1ccc(-c2csc(N(CC(=O)O)Cc3cccs3)n2)cc1

Procedure:
2-{Thiophen-2-ylmethyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}acetic acid hydrochloride was prepared (63 mg) following general procedure G1 using 2-{thiophen-2-ylmethyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}acetic acid tert-butyl ester (66 mg, 0.155 mmol) and 4 N HCl solution in dioxane (1.0 mL). LCMS m/z: 474 (M+1)+.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10](Cl)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:16]3[C:17]([O:21][CH3:22])=[N:18][N:19]([CH3:20])[C:15]=3[NH:14][S:10]([C:9]3[C:4]4[C:5](=[N:1][S:2][N:3]=4)[CH:6]=[CH:7][CH:8]=3)(=[O:12])=[O:11])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2cccc3nsnc23)c1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 3.9 %

Procedure:
To a solution of 4-dimethylaminopyridine in anhydrous pyridine at 0° C. under an atmosphere of nitrogen was added 2,1,3-benzothiadiazole-4-sulfonyl chloride (142 mg) in pyridine (1.5 ml). After 10 min the reaction was treated with 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and the reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was concentrated under reduced pressure, the residue diluted with brine (100 mg) and extracted with dichloromethane (3×50 ml). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (eluent of 55% water in acetonitrile to 30% water in acetonitrile over 8 mins, then 30% water in acetonitrile for 13 mins. Phenomenex Magellen™ 150 mm×21.5 mm column, 40° C.) to yield the title compound as an off-white solid (7 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21]C)=[O:20])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.[OH-].[Na+].CO.Cl>O.O1CCCC1>[NH2:1][C:2]1[N:3]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([OH:21])=[O:20])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: COC(=O)c1cccc(-n2nc3c(c2N)c(=O)[nH]c2ccccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1cccc(C(=O)O)c1
Yield: 82.2 %

Procedure:
A mixture of methyl 3-(3-amino-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzoate (80 mg), an 1N aqueous sodium hydroxide solution (0.5 ml), methanol (5 ml), tetrahydrofuran (5 ml) and water (2.5 ml) was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried to obtain the target compound (63 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[C:13]([C:16]1[C:17](=[O:25])[N:18]([CH3:24])[C:19]([CH3:23])=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:14]>>[OH:22][C:21]1[CH:20]=[C:19]([CH3:23])[N:18]([CH3:24])[C:17](=[O:25])[C:16]=1[C:13](=[O:15])[CH:14]=[CH:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:6]=1
Reactant: O=Cc1cccc(OCCO)c1
Reactant: CC(=O)c1c(O)cc(C)n(C)c1=O
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCO)c2)c(=O)n1C
Yield: 16 %

Procedure:
According to the same manner as that of Example a-1 except that 4.90 g of 3-(2-hydroxyethoxy)benzaldehyde was used in place of 3-[(methoxycarbonyl)methoxy]benzaldehyde, and 4.86 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, 1.41 g of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (40a)] was obtained as a yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([N:1]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2c(c1)CCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: c1cc2c(cc1N1CCNCC1)CCCO2

Procedure:
A solution of 6-aminochroman from part 2 of this example (0.300 g, 2.013 mmol), bis-(2-choroethyl)amine hydrochloride (0.539 g, 3.020 mmol) and potassium carbonate (0.278 g, 2.013 mmol) in 10 mL chlorobenzene is heated at reflux for 24 h. The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic layer is separated, dried over Mg2SO4, filtered and concentrated. Purification by flash column chromatography (5% methanol-methylene chloride) affords 0.157 g (36%) of 1-(chroman-6-yl)piperazine as a white solid, TLC Rf 0.35 (elution with 10% methanol-methylene chloride).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([F:41])[C:39]=1[F:40])[CH2:35]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:35][C:34]3[CH:33]=[C:32]([F:31])[C:39]([F:40])=[C:38]([F:41])[CH:37]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1cc(CBr)cc(F)c1F
Product: Cc1nc2c(ccn2Cc2cc(F)c(F)c(F)c2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3,4,5-trifluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.43 (m, 1 H), 7.24-7.17 (m, 1 H), 7.07 (t, J=3.0 Hz, 1 H), 6.97-6.87 (m, 3 H), 6.35 (dd, J=3.3, 11.3 Hz, 1 H), 5.60-5.42 (m, 3 H), 4.29 (t, J=4.8 Hz, 2 H), 2.92-2.80 (m, 2 H), 2.76 (s, 3 H), 2.15-2.07 (m, 2 H), 1.01-0.91 (s, 9 H); LC/MS (m/z) ES+=539.34 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:12])[C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To the product of Example 3 (5.1 g, 14.2 mmol) dissolved in 100 mL of methanol (MeOH) was added 25 mL (25.0 mmol) of 1N sodium hydroxide (NaOH). This reaction was stirred at room temperature overnight before all solvent was removed under reduced pressure. The residue was dissolved in 250 mL of water and the solution was brought to pH 3 with 1N HCl. The product was extracted from the aqueous phase with 3×250 mL of Et2O. The Et2O layer was then dried (Na2SO4), filtered, and stripped of all solvent under reduced pressure to provide 4.7 g of the title compound after drying in a vacuum oven.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][OH:15])[C:7]2=[O:12].[OH-].[K+].I[CH2:19][CH3:20].C(OCC)C>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][O:15][CH2:19][CH3:20])[C:7]2=[O:12]
Reactant: O=C1c2cccc(Br)c2CCN1CCO
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOCCN1CCc2c(Br)cccc2C1=O
Reaction time: 0.5 h

Procedure:
0.363 g of 5-bromo-2-(2-hydroxyethyl)-3,4-dihydroisoquinolin-1(2H)-one is dissolved under an inert atmosphere in 3 cm3 of dimethylsulfoxide at a temperature close to 20° C. 98 mg of finely ground potassium hydroxide are added. The reaction mixture is stirred for 30 min at a temperature close to 20° C., then 0.131 cm3 of iodoethane is introduced. The stirring is continued for 20 h at a temperature close to 20° C. 50 cm3 of a water/ice mixture and 80 cm3 of ethyl ether are added. After decanting, the organic phase is washed with 3 times with 10 cm3 of water, 30 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator under reduced pressure (5 kPa). 356 mg of 5-bromo-2-(2-ethoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[N+:15]([CH3:18])([O-:17])=[O:16].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:18][N+:15]([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccc(OC)cc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1
Reaction time: 72 h

Procedure:
A mixture of 288 g of 4-methoxycinnamic acid methyl ester, 500 g of nitromethane and 23 g of tetramethylguanidine is allowed to stir for 72 hours. The solution is diluted with diethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-methoxyphenyl)butanoic acid methyl ester.
Reaction SMILES: [NH:1]=[C:2]([C:7]#[N:8])[C:3](=[NH:6])[C:4]#[N:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](N)=[C:12](N)[CH:11]=1.FC(F)(F)C(O)=O>O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[N:6]=[C:3]([C:4]#[N:5])[C:2]([C:7]#[N:8])=[N:1]2
Reactant: N#CC(=N)C(=N)C#N
Reactant: Nc1ccc(Cl)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1nc2ccc(Cl)cc2nc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A mixture of 0.5 g (4.7 mmols) of the diiminosuccinonitrile and 0.67 g (4.7 mmols) of 4-chloro-1,2-phenylenediamine was slowly added to 10 ml of trifluoroacetic acid at about 20° C. over a period of 30 minutes, and the resulting mixture was stirred at room temperature for 8 hours and then allowed to stand overnight. To the reaction mixture was added 50 ml of water, and the solid precipitated was filtered and sufficiently washed with water. The solid thus obtained was dried under reduced pressure, followed by a silica gel column chromatography (eluent: hexane/ethyl acetate (75/25)) and then recrystallization from chloroform/ethanol, wherein 0.6 g (59%) of 6-chloro-2,3-dicyanoquinoxaline was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N:10]1C(C)=CC(O)=CC1=O.FC1C=C(F)C=CC=1CBr.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(#N)C.O>[NH2:10][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:8][OH:9]
Reactant: Cc1cc(O)cc(=O)n1-c1cc(CO)ccc1Cl
Agent: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(CO)ccc1Cl
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1-[2-chloro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(1H)-one (from step 2) (3.5 g, 13.2 mmol) was taken up in DMF (10 ml) and cooled to 0° C. 2,4-Difluorobenzyl bromide (1.7 ml, 13.2 mmol) and K2CO3 (1.8 g, 13.2 mmol) were added and the reaction stirred for 6 hours. The reaction was worked up by adding saturated NaHCO3 (aq.) and extracting with ethyl acetate. The ethyl acetate extraction was washed with water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, filtered, and the solvent removed in vacuo. The product was obtained in 83% crude yield and carried through to the next step as a brown oil. LC/MS, tr=2.48 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 392 (M+H). ES-HRMS m/z 392.0853 (M+H calcd for C20H17ClF2NO3 requires 392.0860).
Reaction SMILES: [CH3:1][C:2]1C=C[C:5](S(Cl)(=O)=O)=[CH:4][CH:3]=1.C(O)CCC#C.N1C=CC=CC=1.CC1C=CC(S(OCCCC#C)(=O)=O)=CC=1.[O:40]=[CH:41][C:42]1[CH:50]=[CH:49][C:47]([OH:48])=[C:44]([O:45][CH3:46])[CH:43]=1>C(Cl)Cl>[CH3:46][O:45][C:44]1[CH:43]=[C:42]([CH:50]=[CH:49][C:47]=1[O:48][CH2:5][CH2:4][CH2:3][C:2]#[CH:1])[CH:41]=[O:40]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: C#CCCCO
Agent: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCCCOc1ccc(C=O)cc1OC
Yield: 89.5 %

Procedure:
4-Methylbenzenesulfonyl chloride (5.7 g, 30 mmol), 4-pentyn-1-ol (1.8 mL, 20 mmol) and pyridine (3.2 mL, 40 mmol) in CH2Cl2 (20 mL) were treated according to Procedure 4 giving pent-4-ynyl 4-methylbenzenesulfonate (4.60 g, 97%) as a colourless oil. Vanillin (0.98 g, 6.4 mmol) was alkylated with pent-4-ynyl 4-methylbenzenesulfonate (2.3 g, 8.3 mmol) according to Procedure 4 and the crude product was recystallised from EtOAc/petrol to provide 3-methoxy-4-(pent-4-ynyloxy)benzaldehyde (1.25 g, 89%) as a colourless crystalline solid; mp 91-92° C.; δH (400 MHz, CDCl3) 1.98 (t, J=2.8 Hz, 1H, C≡CH), 2.09 (p, J=7.0 Hz, 2H, CH2), 2.43 (td, J=7.0, 2.8 Hz, 2H, CH2C≡CH), 3.91 (s, 3H, OCH3), 4.21 (t, J=7.0 Hz, 2H, OCH2), 6.99 (d, J5,6=8.0 Hz, 1H, H5), 7.40 (s, 1H, H2), 7.43 (d, J5,6=8.0 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 15.1, 27.8, 56.0, 67.3, 69.1, 83.1, 109.3, 111.5, 126.7, 130.1, 149.9, 153.9, 190.8; vmax 1028, 1265, 1583, 1674, 2956, 3214 cm−1.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][CH2:3]1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:4][CH2:3]1
Reactant: CC1(C)CN=C(c2ccccc2)c2ccccc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC1(C)CNC(c2ccccc2)c2ccccc21
Yield: 4 %

Procedure:
A solution of 471 mg (2.0 mmol) of 4,4-dimethyl-1-phenyl-3,4-dihydroisoquinoline in MeOH (6 ml) was cooled to 0° C. and 151 mg (4.0 mmol) of NaBH4 were added in portions. After stirring for 3 h at RT a saturated aqueous NH4Cl solution was added. Then most of the methanol was removed under vacuum and the residue was extracted with EE. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 19 mg (0.08 mmol, 4%) of 4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]2=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][N:9]=[C:5]2[CH:4]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:1]([C:3]1[CH:17]=[CH:16][C:6]2=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][N:9]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(-c3ccccc3)onc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc2c(-c3ccccc3)onc2c1

Procedure:
A mixture of 1.9 g (0.0085 mole) of 6-ethyl-3-phenyl-2,1-benzisoxazole, 1.5 g (0.0087 mole) of N-bromosuccinimide and a few crystals of dibenzoyl peroxide in 100 ml of carbon tetrachloride was heated at reflux for 2 hr under floodlight illumination and under an argon atmosphere. The cooled reaction mixture was filtered, and the filtrate was washed twice with 100 ml portions of 10% sodium bicarbonate solution, once with water (100 ml) and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated to a dark brown oil which solidified upon standing. The solid was purified by chromatography (3.5×60 cm glass column; 180 g of silica gel; benzene). Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give a viscous oil which solidified upon standing. The solid was recrystallized from diethyl ether-petroleum ether (30°-60° C.) to give 1.7 g (65%) of mustard yellow crystals, m.p. 99°-102° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:12]N1C(=O)CCC1=O>C(#N)C.C(Cl)(Cl)Cl>[Br:12][C:4]1[NH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1[nH]cnc1C
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]c(Br)nc1C
Reaction time: 20 h
Yield: 62.1 %

Procedure:
To a stirred suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (2.00 g, 13.0 mmol) in acetonitrile (25 mL) and chloroform (25 mL) was added N-bromosuccinimide (2.31 g, 13.0 mmol). The reaction mixture was stirred under nitrogen atmosphere for 20 h, then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate as a light yellow solid (1.88 g, 62%): 1H NMR (300 MHz, CDCl3) δ 4.35 (q, J=7.1 Hz, 2H), 2.51 (s, 3H), 1.37 (t, J=7.1 Hz, 3H); MS (ES+) m/z 233.1 (M+1), 235.1 (M+1).