Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-:3])=[O:2].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[N+:17]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:13]([Cl:14])[CH:12]=[C:11]2[C:6]=1[NH:7][C:8](=[O:16])[C:9](=[O:15])[NH:10]2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c([N+](=O)[O-])c2[nH]c1=O
Temperature: 4 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
To a solution of 6-nitro-7-chloro-1,4-dihydro-2,3-quinoxalinedione (120 mg, 0.50 mmol) in concentrated H2SO4 (1.0 mL) was added KNO3 (61 mg, 0.60 mmol, Baker). The mixture was stirred at 4° C. for 2 days, then ice (2 g) was added. The precipitate was collected by filtration and the solid was dissolved in 1N NaOH (5 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl (~1.2 mL) to give a yellow precipitate, which was collected by filtration and was washed with water (2×1 mL), then was dried at 50° C. for 4 h, affording crude title compound (101 mg, 70%) as a yellow powder. The crude compound (100 mg) was dissolved into acetone (2 mL) and the insoluble material was removed by centrifugation. Water (1 mL) was added to the clear solution of acetone and the resultant solution was allowed to stand at 4° C. overnight to give purer compound. Recrystallization from acetone/water again gave pure title compound (55 mg). Mp: 298°-300° C. (dec.); IR (KBr, cm-1): 3434, 3295, 3111, 2920, 1716, 1571. 1H NMR (DMSO-d6): δ12.560 (s, 1H), 12.421 (s, 1H), 7.442 (s, 1H). HRMS; calcd for C8H3ClN4O6 (M+) m/z: 285.9740, found: 285.9741.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17]C1CCCCO1)[C:9](=O)[CH2:8][CH2:7]2)[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=S)[CH:29]=[CH:30][CH:31]=1.C[Si](C)(C)[Si](C)(C)C.[Li].[NH2:44][NH2:45].C(O)(=O)C>C(OCC)(=O)C.C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][OH:17])[C:9]1=[N:44][NH:45][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)=[C:8]1[CH2:7]2)[CH3:2]
Reactant: NN
Reactant: Fc1cccc(N=C=S)c1
Reactant: CCOc1cc2c(cc1OCCCOC1CCCCO1)C(=O)CC2
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc2c(cc1OCCCO)-c1n[nH]c(Nc3cccc(F)c3)c1C2

Procedure:
To a mixture of 5-Ethoxy-6-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one, (Intermediate Z) (0.100 g, 0.0003 mol), 3-fluorophenyl isothiocyanate (Compound 4a) (0.043 mL, 0.00036 mol) and THF (3 mL) was added lithium hexamethyldisilane (0.360 mL, 0.00036 mol) dropwise at room temperature with stirring. The reaction mixture was stirred for 5 h. Hydrazine (0.011 mL, 0.00036 mol) and acetic acid (0.021 mL, 0.00036 mol) was added to the reaction mixture, which was then heated at reflux temperature for 12 h. The reaction solution was then diluted with ethyl acetate, washed with water and dried over MgSO4. The solvent was removed in vacuo and the crude material was purified on the reverse phase HPLC and converted to the desired product upon standing in the 0.1% TFA solution. Lyophilization yielded the title compound as a white powder. MS m/z 384.4 (M+H)+;
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH:31]([Zn]C(C)C)([CH3:33])[CH3:32]>C1(C)C=CC=CC=1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH:31]([C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:7]3[C:6]=2[CH:5]=1)([CH3:33])[CH3:32]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc2c1C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: CC(C)[Zn]C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)C)cc2c1C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans tert-butyl 6-methyl-5-oxo-8-(trifluoromethylsulfonyloxy)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 91, Part A (265 mg, 0.59 mmol) was added diisopropylzinc (1.76 mL of a 1.0 M solution in toluene, 1.76 mmol). The reaction mixture was degassed with a stream of argon and then there was added bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (22 mg, 0.029 mmol). The reaction mixture was allowed to stir at 65° C. for 18 h. The reaction was allowed to cool to ambient temperature and was quenched with 1N HCl. The mixture was diluted with ethyl acetate and the organics were washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 0.22 g of the title compound as an off-white solid, which was sufficiently pure to be employed directly in Part B. LRMS (ESI): 345.2 (M+H)+.
Reaction SMILES: C([N:6]([CH3:13])[NH:7][C:8]([NH:10][CH:11]=O)=[S:9])(OCC)=O.[OH-:14].[K+].S(=O)(=O)(O)O.[CH2:21]([OH:23])C>>[C:21]([CH2:11][N:10]1[CH:13]=[N:6][N:7]=[C:8]1[SH:9])([OH:23])=[O:14]
Reactant: CCOC(=O)N(C)NC(=S)NC=O
Reactant: [OH-]
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)Cn1cnnc1S

Procedure:
1-carbethoxy-methyl-4-formylthiosemicarbazide (0.50 g., 2.44 mmol.) was dissolved in 5 ml. of ethanol and 5 ml. (2 equivalents) of aqueous potassium hydroxide solution was added. The reaction mixture was refluxed for five hours then cooled, acidified to pH 2.0 with 6N sulfuric acid and evaporated to dryness. The residue was extracted with acetone to give 4-carboxymethyl-1,2,4-triazole-3-thiol.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:11]=1[O:12][C:13]1[N:18]=[C:17]2[NH:19][N:20]=[CH:21][C:16]2=[C:15]([NH:22][CH2:23][C@H:24]([OH:26])[CH3:25])[N:14]=1>CN(C=O)C>[F:9][C:10]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:11]=1[O:12][C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([I:1])[C:16]2=[C:15]([NH:22][CH2:23][CH:24]([OH:26])[CH3:25])[N:14]=1
Reactant: C[C@@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(I)c12
Temperature: 80 °C
Yield: 109.3 %

Procedure:
N-iodo succinimide (35 mg. 0.157 mmol) was dissolved in 3 mL of DMF, and (R)-1-[6-(2,4-Difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (42 mg, 0.131 mmol) was added. The reaction mixture was heated to 80° C. for two hours, after which an additional 35 mg of N-iodo succinimide was added. After heating for two more hours at 80° C., an additional 35 mg of N-iodo succinimide was added. The reaction mixture was heated at 80° C. for 5 more hours, then was cooled to room temperature. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure to give 64 mg of 1-[6-(2,4-Difluoro-phenoxy)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=448.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].[H][H].[C:18](NC(C1CCC(C(O)=O)CC1)C)(=O)C.Cl.CO>N.[C].[Ru].CO>[C:1]([NH:4][CH:5]([CH:7]1[CH2:15][CH2:14][CH:10]([C:11]([O:13][CH3:18])=[O:12])[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)C1CCC(C(=O)O)CC1
Reactant: CC(=O)NC(C)c1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Ru]
Agent: Cl
Agent: N
Solvent: CO
Product: COC(=O)C1CCC(C(C)NC(C)=O)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution (220 ml) of (+)-4-(1-acetamidoethyl)benzoic acid (51.2 g) and 5% ruthenium carbon (35.4 g) in 28% aqueous ammonia was stirred in an autoclave at initial hydrogen pressure of 70 atm and at 90° C. for 3 hours and then at 150° C. for 3 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 53.5 g of a cis- and trans- mixture of (+)-4-(1-acetamidoethyl)cyclohexanecarboxylic acid. Then, a solution of 31% hydrochloric acid-methanol (33 ml) and methanol (200 ml) were added thereto and the mixture was refluxed for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue obtained was poured into ice water and extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 38.0 g of a cis- and transmixture (2:1) of methyl (+)-4-(1-acetamidoethyl)cyclohexanecarboxylate. [α]D =+11.4° (methanol, c=1)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])/[CH:21]=[CH:22]/[C:23]([O-])=[O:24].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:28]([O:27][C:20](=[O:26])[CH:21]=[CH:22][C:23](=[O:24])[NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[CH3:29]
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 23.5 %

Procedure:
To an ice cold solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline and 0.216 g of monoethyl fumarate in 3 mL of dry dimethylformamide was added 0.288 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl (EDAC). 7-Amino-4-(3-bromoanilino)-quinazoline can be made by methods well-known to those skilled in the art. See, for example, J Med Chem, 1995:3482, which is hereby incorporated by reference. After stirring at 5° C. for 5 minutes, the ice bath was removed, and the reaction was permitted to warm to room temperature where it stirred for 15 hours. The reaction was poured into cold water, and the suspension was made basic with the addition of a saturated sodium bicarbonate solution. The resulting solid was collected by filtration, washed with water, and then recrystallized from 50 mL of ethanol to afford 0.052 g of the desired product, mp >260° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][N:6]([C:11](=[O:41])[C@H:12]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])[N:13]([N+:31]([O-])=O)[S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])[CH2:7][CH2:8][O:9][CH3:10])[CH3:2].C(O)(=O)C.[H][H]>C(O)C.[Pd]>[N:13]#[N:31].[CH2:1]([O:3][C:4](=[O:42])[CH2:5][N:6]([C:11](=[O:41])[C@H:12]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40])[NH:13][S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])[CH2:7][CH2:8][O:9][CH3:10])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)N([N+](=O)[O-])S(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Product: N#N
Yield: 91 %

Procedure:
To a solution of 3.00 g of NG -nitro-N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-ethyl ether gave 2.53 g (91%) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8](=O)[NH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:14]>>[C:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(=O)[nH]c1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cnc(Cl)nc1

Procedure:
200 mL POCl3 and 14 g (0.09 mol) 5-tert-butylpyrimidin-2(1H)-one are heated in a sealed glass ampoule for 3 h at 160° C. The mixture is cooled and the excess
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[CH3:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]=O>>[CH2:49]([O:48][C:46](=[O:47])[C:45]1[CH:44]=[CH:43][C:40](/[CH:41]=[C:15](/[C:7]2[CH:6]=[CH:5][C:4]3[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=3[CH:8]=2)\[CH3:16])=[CH:39][C:38]=1[CH3:37])[CH3:50]
Reactant: CCOC(=O)c1ccc(C=O)cc1C
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1C

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 3-methyl-4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-2-methyl-benzoic acid ethyl ester as a colourless oil which is uniform according to thin-layer chromatography, (Rf=0.6; hexane/15% ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:18])([CH3:17])[C:12](OCC)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:20][NH2:21]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:18])([CH3:17])[C:12]([NH:20][NH2:21])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(OC)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ccc(C(C)(C)C(=O)NN)cc1OC
Reaction time: 12 h
Yield: 102.5 %

Procedure:
A solution of ethyl 2-(3,4-dimethoxyphenyl)-2-methylpropanoate (2.84 g, 11.26 mmol) and hydrazine hydrate (7.00 mL, 112.56 mmol) in MeOH (15 mL) was heated at 110° C. in a sealed tube. After 12 h, additional hydrazine hydrate (10 mL) was added to the reaction mixture, which then was heated for additional 6 h. The cooled mixture was concentrated to afford 2-(3,4-dimethoxyphenyl)-2-methylpropanehydrazide (2.75 g, quant) as a liquid. 1H NMR (400 MHz, CDCl3) δ 6.94-6.91 (m, 1H), 6.87-6.81 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.69 (br s, 3H), 1.56 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:12]=[N:11][N:10]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>C(#N)C>[CH3:28][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:12]=[N:11][N:10]=1)=[O:40])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCn1nnnc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCn1nnnc1NC(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 23.7 %

Procedure:
Triethylamine (2.50 mL, 18.0 mmol) was added to a slurry of 5-amino-1-dodecyltetrazole (4.56 g, 18.0 mmol) in acetonitrile (150 mL). The mixture was heated to reflux and upon dissolution of the solid, 2,6-diisopropylphenyl isocyanate (3.90 mL, 18.1 mmol) was added in one portion. The solution was refluxed for 18 hours and allowed to cool. The resultant precipitate was filtered and the filtrate concentrated in vacuo and partitioned between ethyl acetate and water (1:1). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and columned on silica gel, eluting with 10% then 15% ethyl acetate in hexanes to give an oil which solidified on standing to give the title compound as a white solid (1.95 g, 24%), m.p. 80-88° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)([O-:12])=[O:11]>O.[OH-].[Na+].C1C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:21])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)C[C@H](NC(=O)Nc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 2 h
Yield: 79.4 %

Procedure:
4.56 g (0.0568 mol) of L-aspartic acid are dissolved in water by addition of sodium hydroxide until a pH close to 10 is obtained. A solution of 10 g (0.0568 mol) of 4-nitrophenyl isocyanate in 50 cm3 of benzene is then added at room temperature. The solution is stirred vigorously for two hours whilst maintaining the pH at around 10 by successive addition of a concentrated sodium hydroxide solution. The weak precipitate formed is eliminated by filtration and the filtrate is washed with 3×50 cm3 of ethyl ether. The aqueous phase is then acidified and extracted with ethyl acetate, which makes it possible to obtain, after drying over anhydrous sodium sulfate and after concentration, 13.4 g (yield 76%) of a yellow solid of which the melting point is 118°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.S(=O)=O.C1COCC1.[S:29](Cl)([Cl:32])(=[O:31])=[O:30]>C(OCC)C.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:29]([Cl:32])(=[O:31])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccccc1OCc1ccccc1
Agent: O=S=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To 2-benzyloxy-1-bromo benzene (4.0 g, 15.2 mmol) in diethyl ether/THF (1:1, 100 mL) at −78° C. was added n-butyllithium (2 equiv.). After 30 min sulfur dioxide/THF (1:1, 40 mL) was added. The reaction warmed to room temperature over 1.5 h and the solvent was removed under reduced pressure. Hexanes (75 mL) was added and the reaction was cooled to 0° C. prior to adding sulfuryl chloride (2 equiv.). After 15 min the reaction was poured into water, washed with brine and dried over magnesium sulfate to give a colorless oil. Chromatography silica gel, eluting with 1:1 hexanes/diethyl ether gave 2-benzyloxy-benzenesulfonyl chloride (3.11 g, 72%) as a colorless solid. 1H NMR (CDCl3) 8.00(d,1H), 7.65(t,1H), 7.54(d,2H), 7.38(m,3H), 7.12(m,2H), 5.37 (s,2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:11].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Br-:1].[Br:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCCCCCCCCBr
Solvent: Cc1ccccc1
Product: BrCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 60 °C
Reaction time: 10 h

Procedure:
103 g (0.36 mol) 1,9-dibromononane is stirred at 120° C. and a solution of 11.8 g (0.045 mol) triphenylphosphine in 120 ml toluene is added within 8 hours. After a further 10 hours at 120° C. it is allowed to cool, the supernatant is decanted and the viscous residue is stirred twice with isohexane at 60° C. After drying on a rotary evaporator in a stream of nitrogen 22.4 g (91%) 65 was obtained as a nearly colourless resin.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:5]=[C:6]2[C:15]=1[CH:14]=[CH:13][C:12]1[O:11][CH2:10][CH2:9][O:8][C:7]2=1.[C:23](B1OC(C)(C)C(C)(C)O1)([CH3:25])=[CH2:24]>>[CH:23]([C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:5]=[C:6]2[C:15]=1[CH:14]=[CH:13][C:12]1[O:11][CH2:10][CH2:9][O:8][C:7]2=1)([CH3:25])[CH3:24]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(Nc2cc3c4c(ccc3c(Cl)n2)OCCO4)n[nH]1
Product: Cc1cc(Nc2cc3c4c(ccc3c(C(C)C)n2)OCCO4)n[nH]1

Procedure:
Similar procedure as described in example 330 was used, starting from (8-Chloro-2,3-dihydro-1,4-dioxa-7-aza-phenanthren-6-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropenylboronic acid pinacol ester to give (8-Isopropyl-2,3-dihydro-1,4-dioxa-7-aza-phenanthren-6-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 325(MH+).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[C:28]([CH:30]=[O:31])[C:27]([O:32][CH2:33][O:34][CH3:35])=[C:26]([C:36]([O:38][CH3:39])=[O:37])[CH:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8].[O:40]1CCC[CH2:41]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[C:28]([CH:30]=[O:31])[C:27]([O:32][CH2:33][O:34][CH3:35])=[C:26]([C:36]([O:38][CH2:39][O:4][CH3:2])=[O:37])[CH:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[C:28]([CH:30]([OH:31])[CH:2]([OH:4])[CH3:1])[C:27]([O:32][CH2:33][O:34][CH3:35])=[C:26]([C:36]([O:38][CH2:39][O:40][CH3:41])=[O:37])[CH:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8]
Reactant: C1CCOC1
Reactant: CCOc1ccc(-c2nc(-c3cc(C=O)c(OCOC)c(C(=O)OC)c3)cs2)cc1OCC
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)OCOC)c(OCOC)c(C(O)C(C)O)c3)cs2)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cc(C=O)c(OCOC)c(C(=O)OCOC)c3)cs2)cc1OCC

Procedure:
535 mg of methyltriphenylphosphonium bromide was suspended in 10 ml of tetrahydrofuran with stirring. Thereto was added 190 mg of potassium tert-butoxide at -5° C., and the mixture was stirred at the same temperature for 1 hour. Thereto was added 500 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole. The mixture was stirred at the same temperature for 2 hours and at room temperature for 1 hour. To the reaction mixture were added 30 ml of ethyl acetate and 20 ml of water, and phase separation was conducted. The organic layer was washed with 20 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane/n-hexane=2/1 by v/v) to obtain 240 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-hydroxy-5-vinylphenyl)thiazole (A) and 120 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-vinylphenyl)thiazole (B).