Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[O-:11][S:12]([O-:14])=O.[Na+].[Na+].C(Cl)(=O)C(Cl)=O.[CH3:23][NH2:24]>CCO.O.[Cl-].[Na+].O.CCOC(C)=O>[C:6]([C:5]1[CH:4]=[C:3]([CH2:2][S:12]([NH:24][CH3:23])(=[O:14])=[O:11])[CH:10]=[CH:9][CH:8]=1)#[N:7]
Reactant: O=S([O-])[O-]
Reactant: CN
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)Cc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
A solution of 3-bromomethyl-benzonitrile (2 g, 10.2 mmol) in EtOH (50 mL) is treated with a solution of Na2SO3 (1.3 g, 10.3 mmol) in H2O (50 mL) and heated at reflux for 4 hours. The mixture is concentrated in vacuo. The residue is suspended in DCM (100 mL) and DMF (1 mL), cooled to 0° C. and treated with oxalyl chloride (8 mL, 43.4 mmol). The mixture is warmed to room temperature and stirred for 3 hours. The mixture is diluted with brine, extracted with DCM (2×100 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is dissolved in THF (25 mL), methylamine (2 M, 12.5 mL, 25 mmol) is added and the mixture is stirred for 12 hours. The mixture is diluted with EtOAc (100 mL), washed with saturated aqueous NH4Cl (2×100 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford C-(3-cyano-phenyl)-N-methyl-methanesulfonamide (1.5 g, 69%) as a powder. MS: 209 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.60 (d, J=4.8 Hz, 3H), 4.44 (s, 2H), 7.02 (m, 1H), 7.61 (m, 1H), 7.74 (m, 1H), 7.85 (m, 2H).
Reaction SMILES: C[NH:2][C@H:3]([C:12]([O-:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1C=CC=C[CH:16]=1.C[Si](Cl)(C)C.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37].Cl>C(Cl)Cl>[CH3:16][O:14][C:12](=[O:13])[C@@H:3]([NH:2][S:36]([C:27]1[CH:28]=[CH:29][C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=1)(=[O:38])=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: c1ccncc1
Reactant: CN[C@@H](Cc1ccc(O)cc1)C(=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Methyltyrosinate(1 g, 4.32 mmol) was suspended in 5 ml of methylene chloride, pyridine(1.4 ml, 17.28 mmol) was added thereto, and the reaction mixture was allowed to stand until the mixture became thoroughly transparent. After the reaction solution became transparent, trimethylsilylchloride(1.1 ml, 8.64 mmol) was slowly added thereto at room temperature. After 1 hour, 2-naphthalenesulfonylchloride(1.08 g, 4.75 mmol) was added and the resulting mixture was stirred for 24 hours. To this mixture was added 3N HCl solution, which was then stirred for about 2 hours. The organic layer was separated, the aqueous layer was extracted with methylene chloride, and the organic layers were combined. The combined organic layer was dried over Na2SO4 and the organic solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from toluene to give 1.29 g(Yield 79%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:28]2[CH:27]=[CH:26][C:25]([N+:30]([O-:32])=[O:31])=[CH:24][C:23]=2[F:22])=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2]
Reactant: CCc1ccc(O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 80 °C

Procedure:
A mixture of 4-(2-ethyl-5-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (135 mg, 0.47 mmol), 3,4-difluoro-1-nitrobenzene (90 mg, 0.56 mmol), and potassium carbonate (130 mg, 0.94 mmol) in N,N-dimethylformamide (3 ml) is heated to 80° C. for 3 hours. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-[2-ethyl-5-(2-fluoro-4-nitrophenoxy)phenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:35][CH3:36])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:18]>>[CH2:35]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c1C
Yield: 56.4 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (1.5 g, 7.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (2 g) to give 1.9 g (57%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=O)[O:13][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C@@H:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)[CH:17]=2)=[CH:3]1.C[N:34](C=O)C>N.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:13])[NH:34][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C@@H:24]3[CH2:28][O:27][C:26]([CH3:29])([CH3:30])[O:25]3)[CH:17]=2)=[CH:3]1
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3cccc(OC[C@@H]4COC(C)(C)O4)c3)C(=O)OC2=O)c2ccccc21
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3cccc(OC[C@@H]4COC(C)(C)O4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
3-(1-Methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-phenyl]furan-2,5-dione (5.4 g, 13.7 mmol) was dissolved in DMF (50 mL) and was diluted with NH3 (aq.) (100 mL). The reaction mixture was then heated at 140° C. for 5 h, cooled to room temperature and then diluted with water. The product was extracted with EtOAc and the organic layer was washed with NaCl (sat.) and dried over sodium sulfate to give the crude product which was further purified by re-crystallization from dichloromethane and hexane to give 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dione (5 g).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[ClH:20].[CH2:1]([O:8][N:9]=[C:10]([Cl:20])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cccnc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClC(=NOCc1ccccc1)c1cccnc1
Yield: 62 %

Procedure:
2.38 g (10 mmoles) of N-(benzyloxy)nicotinamide (Beilstein 22/V, page 120) are boiled under reflux in 20 ml of thionyl chloride for 2 hours. After distilling off the excess thionyl chloride, the residue is crystallized from isopropanol to give 1.75 g (62%) of the desired product, the physical characteristics of which are identical to those of the product prepared by method A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:34][C@@H:35]1[C:53](=[O:54])[N:37]2[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][S:43][C:44]3[S:45][C:46]([CH3:49])=[N:47][N:48]=3)[CH2:40][S:41][C@H:36]12>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([NH:34][C@@H:35]2[C:53](=[O:54])[N:37]3[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][S:43][C:44]4[S:45][C:46]([CH3:49])=[N:47][N:48]=4)[CH2:40][S:41][C@H:36]23)=[O:18])=[CH:12][CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cc4ccc(CNC(=O)OC(C)(C)C)s4)[C@H]3SC2)s1
Reaction time: 4 h

Procedure:
The starting material is prepared as follows: A solution of 4.08 g of 2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid in 200 ml of methylene chloride containing 1.65 ml of 4-methyl-morpholine is cooled to -20° under exclusion of moisture and treated dropwise with 1.95 ml of chloroformic acid isobutyl ester. After 30 minutes a solution of 5.16 g of 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid and 7.20 ml N,O-bis-(trimethylsilyl)-acetic acid amide in 150 ml of methylene chloride is added, whereupon the reaction mixture is stirred during one hour at -20° and during four hours while the temperature is allowed to slowly rise to room temperature and is then evaporated under reduced pressure. The residue is dissolved in water with the addition of sodium hydrogen carbonate until the pH reaches 8. The solution is washed with ethyl acetate, the separated aqueous layer is acidified to pH 2 with aqueous phosphoric acid of 20% strength and is extracted with ethyl acetate. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. One thus obtains the 7β-[2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid; thin layer chromatogram (silicagel): Rf=0.40 (system: n-butanol/acetic acid/water 45:45:10), ultraviolet absorption spectrum (ethanol): λmax 244 mμ (ε=16900); infrared absorption spectrum (in mineral oil): characteristic bonds at 2.93μ, 5.60μ, 5.90μ, and 6.55μ.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([O:33]C)=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:35][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH2:5][CH2:4]1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([OH:33])=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:35][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:18])=[O:19])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
Methyl (1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 177, 0.279 g) and lithium hydroxide monohydrate (0.233 g) were suspended in dioxane (7 mL) and water (3 mL) and the mixture was stirred and heated at 80° C. for 25 hours. Further lithium hydroxide monohydrate (0.116 g) was added and the mixture heating was continued for 18 hours. After cooling, the volatiles were removed in vacuo, the residue was acidified by addition of aqueous citric acid solution (10%) and saturated with sodium chloride. The mixture was extracted with DCM and the organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.117 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:10])[N:4]([CH3:9])[C:5](=[O:8])[C:6]=1[CH3:7].OC1N(C)[N:14](C)[C:15](=O)[C:16]=1C.CC(C(OCC)=O)C(OCC)=O.C[NH:34]NC.P(Cl)(Cl)(Cl)=O>>[NH2:34][CH2:16][CH2:15][NH:14][C:2]1[N:3]([CH3:10])[N:4]([CH3:9])[C:5](=[O:8])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)n(C)n(C)c1=O
Reactant: Cc1c(O)n(C)n(C)c1=O
Reactant: CNNC
Agent: CCOC(=O)C(C)C(=O)OCC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(NCCN)n(C)n(C)c1=O

Procedure:
The 3-chloro-1,2,4-trimethylpyrazol-5-one used as starting material can be obtained in the following manner: 28.6 g. 3-hydroxy-1,2,4-trimethylpyrazol-5-one (m.p. 87°-89° C., after recrystallization from ethyl acetate), prepared from diethyl methylmalonate and N,N'-dimethylhydrazine, are boiled under reflux for 3.5 hours with 55 ml. phosphorus oxychloride. The reaction mixture is then evaporated and the residue is stirred with ice and water, rendered alkaline by the addition of 10N aqueous sodium hydroxide solution and extracted 8 times with 100 ml. amounts of methylene chloride. The combined extracts are then dried and evaporated to give 24.7 g. (76.5% of theory) 3-chloro-1,2,4-trimethylpyrazol-5-one in the form of colorless crystals; m.p. 37°-38° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11](OC)=[N:10][S:9]2(=[O:19])=[O:18])=[CH:4][CH:3]=1.[Si:21]([O:28][CH2:29][CH2:30][C@H:31]([NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:39][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])[CH2:30][CH2:29][O:28][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])=[N:10][S:9]2(=[O:18])=[O:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Reactant: COC1=NS(=O)(=O)C(C)(c2ccc(Br)cc2)C(C)(C)O1
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A solution of 70 mg of 5-(4-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 66 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamine in 1 ml of methylene chloride was stirred under a gentle argon stream, such that the solvent evaporated gradually. After stirring at room temperature overnight, the residue was dissolved in 20 ml of dichloromethane and extracted with 10 ml of 0.5 N aqueous hydrochloric acid and 10 ml of water. The organic phase was dried using a phase separator cartridge (Chromabond® PTS), concentrated by rotary evaporation and dried under high vacuum. This gave the product (113 mg) with a molecular weight of 613.7 g/mol (C27H38BrFN2O4SSi); MS (ESI): m/e=614 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:14])(=[O:3])[CH3:2].[H-].[Na+].Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][CH:13]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[O:14][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[O:8]
Reactant: COC(=O)c1cccc(C(C)=O)c1O
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(C)=O)c1OC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
5.3 g of methyl 3-acetylsalicylate are dissolved in 50 ml of dimethylformamide and the solution is added dropwise to a suspension of 1.26 g of 62.5% sodium hydride in 15 ml of dimethylformamide, and the mixture is stirred for 20 minutes. 5.40 g of methyl 2-bromo-propionate are added dropwise to the mixture and the mixture is heated at 60°-80° C. for 7 hours. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:1) to give 5.10 g of methyl 2-(2-methoxycarbonyl-6-acetylphenoxy)propionate as colorless oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([N:22]([CH:32]([CH3:34])[CH3:33])[C:23]1[N:24]=[C:25]([Cl:31])[C:26]([CH:29]=O)=[N:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:35]([NH:42][CH2:43][CH2:44][OH:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:35]([N:42]([CH2:29][C:26]1[C:25]([Cl:31])=[N:24][C:23]([N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=1)[CH2:43][CH2:44][OH:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(C)N(Cc1ccccc1)c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)N(Cc1ccccc1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
Sodium triacetoxyborohydride (2.65 g) was added to a solution of 5-[benzyl(1-methylethyl)amino]-3-chloropyrazine-2-carbaldehyde (2.42 g), N-benzylethanolamine (1.42 g) and acetic acid (1.43 mL) in acetonitrile (14 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→50% ethyl acetate/hexane) to give the title compound (3.32 g, 94%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].[OH-].[Na+].[F:18][CH:19]([F:29])[C:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]([CH3:28])[N:21]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:25]([C:24]1[C:20]([CH:19]([F:29])[F:18])=[N:21][N:22]([CH3:28])[CH:23]=1)=[O:26]
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 56 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (3.92 g, 0.014 mol) prepared as described in example P5a in xylene (30 g) was added an aqueous sodium hydroxide solution (30%, 2.3 g, 0.017 mol) in parallel to the addition of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (3.2 g, 0.046 mol) dissolved in xylene (10 g) at 56° C. during 2 hours. After complete addition of acid chloride the mixture was stirred 2 hours at 56° C. The solution was washed twice with water (10 and 5 g) and the volatiles were removed from the organic layer under reduced pressure. The resulting crude mass 7.4 g (sticky dark brown oil) was purified by crystallization from a mixture of xylene (7 g) and methylcyclohexene (14 g) to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]amide (5.3 g, 87.8%) as off white solid. m.p: 115-116° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:6][C:7]([OH:12])(C)[CH:8]=[CH:9][N:10]=1)([CH3:3])[CH3:2].[C:13]([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]1([CH2:25]Br)[CH2:22][C:21]1([Cl:24])[Cl:23]>CN(C)C=O>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:13])[CH:8]=[C:7]([O:12][CH2:19][C:20]2([CH3:25])[CH2:22][C:21]2([Cl:24])[Cl:23])[N:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)NC1=NC=CC(C)(O)N1
Reactant: CC1(CBr)CC1(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(C)CC2(Cl)Cl)nc(NC(C)C)n1

Procedure:
8.4 g (0.05 mol) 2-Isopropylamino-6-hydroxy-6-methylpyrimidine, 6.9 g (0.05 mol) K2CO3, 6.9 g (0.05 mol) 1-methyl-2,2-dichlorocyclopropylmethylbromide and 100 ml absolute dimethylformamide are charged in a sulphonation flask and the mixture heated for 26 hours at a bath temperature of 110°. After cooling, the reaction mixture is filtered over diatomaceous earth and concentrated. The resulting orange-red oil is chromatographed on silica gel, using diethylether:n-hexane 1:1 as mobile phase. The title compounds is obtained as a yellow, clear oil, Rf value 0.25.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH:22][C:23]([CH3:27])([CH3:26])[C:24]#[CH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C>[OH:22][C:23]([CH3:27])([CH3:26])[C:24]#[C:25][C:2]1[CH:3]=[N:4][C:5]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C#CC(C)(C)O
Reactant: COC(=O)c1cc(Br)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CC(C)(C)O)cnc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A stirred mixture of 12.6 g of 5-bromo-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid, methyl ester, 3.4 g of 3-hydroxy-3-methyl-1-butyne, 0.02 g of bis(triphenylphosphine)palladium(II)-chloride, 0.04 g of triphenylphosphine, and 0.02 g of cuprous iodide in 300 mL of dry triethylamine is heated at reflux for 72 hours. The reaction is then filtered hot through celite, and the filtering agent is washed with methylene chloride. The combined filtrates were concentrated in vacuo, and the residue is partitioned between dilute aqueous hydrochloric acid and methylene chloride. The organic phase is washed with brine, dried, concentrated in vacuo, and the residue is chromatographed on silica gel using ether-methylene chloride mixtures to afford the desired product, mp 142°-145°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:8].[CH2:15]([O:22][C:23]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53]Br)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:22][C:23]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:12]2[CH2:13][CH2:14][N:9]([CH2:7][CH3:8])[CH2:10][CH2:11]2)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCN(CCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C

Procedure:
Potassium carbonate (1.5 g) and 1-ethylpiperazine (1.0 mL) were added to an acetone (8.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (1.6 g), followed by heating to reflux for 5 hours. After cooling the reaction mixture to room temperature, the insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a yellow oily substance.