Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCO
Solvent: c1ccncc1
Product: COCCCOS(=O)(=O)c1ccc(C)cc1
Yield: 132 %

Procedure:
37.9 g of 3-methoxypropanol and 53.9 g of p-toluenesulfonyl chloride in 50.2 g of pyridine were stirred for 3 hours while the reaction temperature is kept at 0 to 10° C. The product was extracted with ethyl acetate, to give 91.2 g of 3-methoxypropyl tosylate (yield: 89%). 55 g of the obtained 3-methoxypropyl tosylate and 39.0 g of 2,3,3,5-tetramethyl-3H-indole were blended at 120° C. for 3 hours and was cooled to room temperature. 47.7 g of 2,5-bis[(phenylamino)methylene]cyclopentylidenediphenylaminium tetrafluoroborate, 23.0 g of acetic anhydride, 56.9 g of triethylamine, and 220 ml of 2-propanol were added thereto, and the mixture was further stirred at 80° C. for 3 hours. After reaction, the mixture was allowed to cool to room temperature, and 90 ml of water was added thereto. The crystal precipitated was collected by filteration, and was washed sufficiently with water, to give 60.1 g of a cyanine colorant (IR-2) (yield: 80%). 15.0 g of the colorant (IR-2) obtained was dissolved in 90 ml of acetonitrile. The mixture was added dropwise into an aqueous solution containing 6.6 g of KPF6 in 90 g of water at room temperature over 15 minutes, and the resulting mixture was stirred for 2 hours after the dropwise addition. Then, the crystal precipitated was collected by filteration and dried, to give 15.2 g of a cyanine colorant (IR-3) (yield: 95%). Then, 5.0 g of the cyanine colorant obtained (IR-3) was dissolved in 50 ml of chloroform, 3.0 g of manganese dioxide was added thereto, and the mixture was stirred at room temperature for 48 hours. After removal of manganese dioxide by filtration, the filtrate was distilled for removal of chloroform, and the crude crystal obtained was resuspended in 20 ml of ethyl acetate, to give 4.5 g of (A-4) (yield: 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([O-])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[Na+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:28])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([Cl:28])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nnnc2C(=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Temperature: 15 °C

Procedure:
Following the procedure of Example 3, the sodium salt produced in Example 5 is stirred with pyridine in benzene at 6° C. with rapid addition of oxalyl chloride. The mixture is stirred at 15° C. for one half hour, stripped and scrubbed twice with benzene to yield 1-(p-methoxybenzyl)-1H-tetrazole-5-carbonyl chloride.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:32]=O>C(O)=O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[CH3:32])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@H]3CCCN3)cc2c1=O
Reactant: C=O
Solvent: O=CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@H]3CCCN3C)cc2c1=O

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (0.15 g) and 38% aqueous formaldehyde (0.284 ml) were stirred in formic acid (3 ml) at 90° C. for 4 hours and then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate followed by 10% methanol/ethyl acetate+1% aqueous ammonia solution to give the title compound (0.128 g) as a pale yellow foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.70 (m, 3H), 1.99 (m, 1H), 2.14 (s, 3H), 2.21 (m, 1H), 2.40 (s, 3H), 2.61 (m, 1H), 2.85 (m, 1H), 2.96 (m, 1H), 3.99 (m, 1H), 4.10 (m, 1H), 7.52 (m, 2H), 7.60 (s, 1H), 7.73 (d, 1M), 7.85 (s, 1H), 7.91 (d, 1H), 8.20 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1.[Li+].[Br-].P(Br)(Br)[Br:24]>CN(C=O)C>[Br:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(CBr)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 417A (1.50 g, 5.51 mmol) in DMF (18.0 mL) at 0° C. was treated with LiBr (526 mg, 6.06 mmol) and PBr3 (1.64 g, 6.06 mmol), warmed to room temperature, and stirred for 30 minutes. The solution was purified by flash column chromatography on silica gel with 3:7 ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C[Al](C)C.[Br:14][C:15]1[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:14][C:15]1[S:19][C:18]([C:20]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])=[NH:21])=[CH:17][CH:16]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: N#Cc1ccc(Br)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: N=C(Nc1c(Cl)cccc1Cl)c1ccc(Br)s1
Temperature: 90 °C
Reaction time: 5 h
Yield: 103.2 %

Procedure:
To a stirred solution of 2,6-dichloroaniline (1.75 g, 10.8 mmol) in toluene (25 mL, anhyd) was added dropwise a 2.0M solution of trimethylaluminum in toluene (8.0 mL, 16 mmol). After 90 min the reaction mixture was charged with a solution of 5-bromothiophene-2-carbonitrile (3.00 g, 16 mmol) in toluene (20 mL, anhyd) and then heated at 90° C. After 5 h the reaction mixture was allowed to cool to ambient temperature and quenched by addition to a stirred slurry of silica (25 g) in 3:1 CHCl3/MeOH (100 mL). After 30 min the resulting mixture was filtered and the solids rinsed with MeOH and DCM. The combined filtrates were concentrated to afford the title compound (3.9 g, quant) as a pale yellow solid, which was used in the next step without purification. GC-MS (EI): 348, 350, 352.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:48])[C:19]([C:23]3[N:24]=[C:25]([NH:28]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].O>C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:48])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
A mixture of 0.975 g of the product of Example 3 in 4 ml of 50% aqueous formic acid was stirred at 55° C. for 10 minutes and 4 ml of water were added thereto. The mixture was vacuum filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was effloresced with 2 ml of ethanol and was vacuum filtered. The product was washed with ethanol and then with ether to obtain 0.428 g of pure 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-ceph-3-eme-4-carboxylic acid with a syn configuration. RMN (DMSO 60 MHZ) ppm: 2.03 ##STR34## doublet 9.58 J=8HZ (CONH), 6.76 (proton of thiazolic ring)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9](C(OC(C)(C)C)=O)[CH:10]([CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=1)[CH3:11]>C1(OC)C=CC=CC=1>[CH3:8][NH:9][CH:10]([CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=1)[CH3:11]
Reactant: Cc1cc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cnc1N
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(C)C/C=C/c1cnc(N)c(C)c1
Reaction time: 0.75 h
Yield: 12.2 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (17.76 g, 155.76 mmol) was added dropwise, via addition funnel, over 30 min to a cold (0–5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine (1.11 g, 3.47 mmol) in anisole (15 mL). The resulting solution was stirred for 45 min at 0–5° C. and was then concentrated by rotary evaporation. The viscous, brown oil was further dried under high vacuum for 18 h. The crude product was cooled (0–5° C.), basified with 10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL), and extracted with CHCl3 (5×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum yielding a dark-brown oil. The crude product was purified by column chromatography on silica gel (50 g), eluting with CHCl3-CH3OH-Et3N (4:1:1, v/v/v). Selected fractions containing the product (Rf 0.13) were combined and concentrated by rotary evaporation, and the residue was re-chromatographed on silica gel (50 g) eluting with CHCl3—CH3OH (7:3, v/v). Fractions containing the product (Rf 0.12) were combined and concentrated by rotary evaporation. The residue was dissolved in CHCl3, and the CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried affording a yellow oil (0.087 g) which tended to crystallize. The semi-crystalline material was dissolved in a warm solution of hexane containing a small amount of ethyl acetate. The warm solution was decanted from an insoluble gum. The solution was allowed to cool to ambient temperature and was further cooled at 5° C. for 18 h. The resulting crystalline solids were collected, washed with hexane, and vacuum dried at 40° C. for 16 h. The yield was 30.8 mg (4.3%) of a light-yellow powder, mp 78–81° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1>C(O)C>[Br:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([S:31][C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:36][CH:37]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3Br)cc2N)cc1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(OCc4ccccc4Br)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 2g (35 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 157a (75 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (18 mg, 29%). 1H NMR (300 MHz, DMSO-d6), ppm: 0.97 (t, J=7.35 Hz, 3H), 1.72-1.92 (m, 2H) 2.02 (s, 3H), 2.99 (t, J=7.35 Hz, 2H), 5.17 (s, 2H), 6.33 (d, J=6.99 Hz, 1H), 7.16 (d, J=8.46 Hz, 2H), 7.18-7.28 (m, 2H), 7.28-7.51 (m, 5H), 7.60 (dd, J=7.54, 1.65 Hz, 1H), 7.69 (d, J=6.99 Hz, 1H), 7.81 (d, J=8.82 Hz, 1H), 8.39 (d, J=6.99 Hz, 1H), 8.97 (d, J=8.82 Hz, 1H), 9.99 (s, 1H), 11.02 (s, 1H), 14.37 (s, 1H): MS (ESI+) m/z 613M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH3:11])[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: COC(=O)c1ccc(-c2ccccc2)c(C)c1
Yield: 10.1 %

Procedure:
A solution of 4-bromo-3-methyl-benzoic acid methyl ester (1.0 g, 4.36 mmol) and phenylboronic acid (0.64 g, 5.24 mmol) in n-PrOH (15 mL) is treated with 2 M Na2CO3 (4.4 mL), and purged with N2 for 10 min, and Pd(PPb3)4 (25 mg, 0.22 mmol) is then added. The reaction is refluxed overnight. Organic solvent is removed in vacuo, the residue is extracted with CH2Cl2 (30 mL), washed with 10% Na2CO3 (30 mL), H2O (30 mL); dried with Na2SO4 and concentrated. Purification of the crude material by chromatography affords the title compound (0.10 g, 10%).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[Se:17][CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Li]CCCC.[CH:26](N1CCOCC1)=[O:27]>C(OCC)C.CC(OC)(C)C.Cl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[Se:17][C:18]([CH:26]=[O:27])=[CH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: O=CN1CCOCC1
Reactant: CCCC1CCC(c2ccc(-c3ccc[se]3)cc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: CCCC1CCC(c2ccc(-c3ccc(C=O)[se]3)cc2)CC1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
1.48 g (4.47 mmol) of 2-[4-(4-propylcyclohexyl)phenyl]selenophene are initially introduced in 15 ml of diethyl ether, and 4.4 ml (7.0 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 15 min and subsequently cooled to −78° C. 1.4 ml (14.0 mmol) of N-formylmorpholine are added in one portion, and the mixture is warmed to RT and stirred for 24 h. The batch is diluted with MTBE, and 1 N hydrochloric acid is added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is recrystallised from n-heptane. 5-[4-(4-Propylcyclohexyl)phenyl]selenophene-2-carbaldehyde is obtained as a red solid.
Reaction SMILES: [C:1]1([CH2:6][S:7][C:8]([N:10]2[C@@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([C:26]([S:28][CH2:29][C:30]4[S:34][CH:33]=[CH:32][CH:31]=4)=[S:27])[C:12]=3[CH2:11]2)=[S:9])[S:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:37])=[N-]>CCOCC>[C:1]1([CH2:6][S:7][C:8]([N:10]2[C@@H:22]([C:23]([O:25][CH3:37])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([C:26]([S:28][CH2:29][C:30]4[S:34][CH:33]=[CH:32][CH:31]=4)=[S:27])[C:12]=3[CH2:11]2)=[S:9])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H]1Cc2c(n(C(=S)SCc3cccs3)c3ccccc23)CN1C(=S)SCc1cccs1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H]1Cc2c(n(C(=S)SCc3cccs3)c3ccccc23)CN1C(=S)SCc1cccs1
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A mixture of (3R)-2,9-di[(2-thenylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (0.3 g), diazomethane [prepared from N-nitrosomethylurea (1.55 g) and 40% KOH (4.5 ml)] and ether (30 ml) is allowed to stand at 0° C. overnight. Undissolved substances are removed by filtration and the filtrate is concentrated to give the title compound (150 mg, 50%) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]1(=[O:13])[O:12][CH2:11][CH2:10]1.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C1CCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
p-Fluorothiophenol (5 g, 40 mmol) and β-propiolactone (2.8 g, 40 mmol) were dissolved in THF (36 mL of freshly distilled) and then placed in an ice bath. 95% sodium hydride (1 g, 42.9 mmol) was added in small portions over 1 hour. The reaction was allowed to stir at 0° C. for 2 hours, then placed in the freezer overnight. The reaction was quenched with ice chips and then acidified with concentrated hydrogen chloride until a pH of 2. The product was extracted with ethyl acetate (1×200 mL) and dichloromethane (2×200 mL), dried (sodium sulfate) and concentrated to give 3-[(4-fluorophenyl)sulfanyl]propanoic acid (7.08 g, 89%). 1H NMR (CDCl3, 300 MHz): δ 7.42-7.35 (m, 2H), 7.02 (t, 2H, J=8.6 Hz), 4.35 (t, 1H, J=6.2 Hz), 3.10 (t, 2H, J=7.3 MHz), 2.63 (t, 2H, J=7.3 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH3:9])=[CH:3][C:4]([O:6][CH3:7])=[O:5].O[C:11](=[C:14]1C(=O)OC(C)(C)[O:16][C:15]1=O)[CH2:12][CH3:13]>>[CH2:8]([C:2]1[NH:1][C:11]([CH2:12][CH3:13])=[CH:14][C:15](=[O:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:9]
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: CCC(N)=CC(=O)OC
Product: CCc1cc(=O)c(C(=O)OC)c(CC)[nH]1
Temperature: 120 °C
Yield: 44 %

Procedure:
A mixture of methyl 3-aminopentenoate (7.3 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (23.0 g) (obtained as described in J. Org. Chem., 1978, 43, 2087) was heated at 120° C. for 2 hours. The mixture was cooled to ambient temperature and triturated with ether (50 ml). The product was collected by filtration to give methyl 2,6-diethyl-4-oxo-1,4-dihydropyridine-3-carboxylate (5.2 g) as a solid, m.p. 124°-127° C.; NMR (d6 -DMSO): 1.2(t, 6H), 2.3-2.6(m, 4H), 3.7(s, 3H), 5.9(s, 1H), 11.2(s, 1H); mass spectrum (CI, ammonia): 210 (M+H)+ ; microanalysis, found: C, 63.1; H, 7.5; N, 6.7%; C11H15NO3 requires: C, 63.1; H, 7.2; N, 6.7%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(C3C(=O)N(C(C)=O)c4ccccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
A solution of 1-acetyloxindole (251 mg, 1.6 mmol), ( J. Med. Chem. 1986, 1838), in DMF (3 ml) was added to a suspension of sodium hydride (50 mg, 2.4 mmol) in DMF (10 ml) and the mixture stirred for 10 minutes at ambient temperature. 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (108 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), in DMF (3 ml) was added and the mixture stirred for 1.5 hours at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (70/30). The purified product was recrystallised from methylene chloride/ether, collected by filtration, washed with ether and dried under vacuum to give 4-(1-acetyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (77 mg, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])([O-:3])=[O:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:18][CH3:19])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
2-Nitro-4-phenylmethoxy-phenol is methylated by contacting it with a slight molar excess of potassium carbonate and a large molar excess of methyl iodide and tetrabutylammonium bromide (TBAB) in an inert solvent (such as acetone) and refluxed for 8 to 15 hours, preferably 12 hours. After cooling, filtration and evaporation of the solvent, the residue is purified by conventional means to give 2-nitro-4-phenylmethoxyanisole, which in turn is hydrogenated to give the corresponding aniline of Formula 12.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][NH:23][C:24]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:25])[CH2:17]1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:24]([NH:23][CH2:22][CH:18]2[O:19][CH2:20][CH2:21][N:16]([CH2:15][C:14]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:12]([Cl:11])[CH:13]=3)[CH2:17]2)=[O:25])[CH2:28][CH2:29]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCN(C(=O)c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
Benzoyl choride (0.014 ml) was added to a solution of Intermediate 16 (0.04 g) and N,N-diisopropylethylamine (0.048 ml) in dichloromethane (3 ml). The solution was stirred for 5 h at 23° C. The solvent was removed in vacuo and the residue purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was concentrated in vacuo and the residue was further purified using a silica gel solid phase extraction cartridge (1 g Varian Bond Elut), eluting sequentially with dichloromethane, ethyl acetate, acetone, acetonitrile, and methanol, to give the title compound as a clear gum (0.024 g).
Reaction SMILES: [CH3:1][C:2]1[C:15]2[NH:14][S:13](=[O:17])(=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:1][C:2]1[C:15]2[N:14]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[S:13](=[O:17])(=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C)c2c1NS(=O)(=O)c1ccccc1-2
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2c3c(C)ccc(C)c3-c3ccccc3S2(=O)=O)cc1
Temperature: 60 °C

Procedure:
1,4-Dimethyl-10H—9-thia-10-aza-phenanthrene 9,9-dioxide (2.6 g, 10 mmol) is dissolved in pyridine (10 mL) and treated with p-toluenesulfonyl chloride (2.8 g, 15 mmol). The reaction mixture stirred at 60° C. until TLC shows disappearance of the starting material. The reaction mixture is allowed to cool and then poured into 100 mL of 3N HCl. The mixture is extracted 2×100 mL EtOAc and the combined organic layers are washed with sat. brine, dried over MgSO4, filtered, and concentrated to a solid, which is recrystallized from hot EtOAc/hexanes to give 1,4-dimethyl-10-(toluene-4-sulfonyl)-10H-9-thia-10-aza-phenanthrene 9,9-dioxide.