Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N:11]([CH2:12][CH2:13][OH:14])[CH3:10])[N:7]=1
Reactant: CNCCO
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCO
Product: Cc1cc(N(C)CCO)nc(Cl)n1
Yield: 34.5 %

Procedure:
Part A: A solution of 2,4-dichloro-6-methylpyrimidine (1.0 g) and 2-(methylamino)ethanol (0.4 g) in ethanol (50 mL) was refluxed for 24 hours. The solvent was evaporated to give a crude residue, which was chromatographed on silica gel using 5% methanol in chloroform to yield 2-chloro-4-methyl-6-(N-methyl-2-hydroxyethylamino)pyrimidine (370 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:40])=[O:41])=[CH:37][CH:38]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCCc3ccc(S(N)(=O)=O)cc3)n2)cc1
Yield: 49 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (30 mg, 49% yield.) MS/ES+: m/z=514.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:12]2=3)(=[O:10])=[O:9])[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1>>[CH2:35]([O:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:22]([C:20]2[CH:19]=[CH:18][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:25][CH3:26])(=[O:9])=[O:10])[C:12]=3[CH:21]=2)=[O:23])=[CH:38][CH:37]=1)[CH3:36]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCCc2ccc(C(=O)O)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCCC3)cc1

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxylic acid was reacted with ethyl 4-aminobenzoate in analogy to example 62, step 4, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carbonyl]-amino}-benzoic acid ethyl ester. Light brown solid, MS (ISP) 543.2 (M+H).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH:8]([OH:20])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][OH:19])[CH:10]=1)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH2:5][CH2:6][CH2:7][CH:8]([C:9]1[CH:10]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][OH:19])[CH:12]=[CH:13][CH:14]=1)[OH:20]
Reactant: O=C(NCCC(O)c1cccc(C#CCCO)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NCCC(O)c1cccc(C#CCCO)c1

Procedure:
A mixture of, 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-hydroxybut-1-ynyl)phenyl)propyl)acetamide, potassium carbonate (1.6 g, 11.5 mmol) and water (3 mL) in MeOH (15 mL) was heated under reflux for 4 h. Reaction mass was concentrated to dryness under reduced pressure to give 4-(3-(3-amino-1-hydroxypropyl)phenyl)but-3-yn-1-ol as pale yellow oil after purification by flash chromatography with 15% MeOH—NH3 (9.5:0.5)-DCM. Yield (0.38 g, 60%). This compound was utilized as such for the next transformation.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>C1COCC1.C(OCC)(=O)C.CO.[Pd]>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)=[CH:18][CH:17]=1
Reactant: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)n(C)c(=O)c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc2nc(CCc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 3,5-dimethyl-2-[2-[4-(4-trifluoromethylbenzoyl)phenyl]vinyl]-4(3H)-quinazolinone (897 mg) in THF: ethyl acetate: methanol (1:1:1) (60 ml) was added 10% Pd/C (50% hydrous) (179 mg) and the mixture was stirred under hydrogen at room temperature for 2 hours. The catalyst was then filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate =2:1) and recrystallized from ethyl acetate-methanol to provide 307 mg of white powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[OH:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH2:3][CH2:2][O:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCCOC1CCCCO1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A suspension of 10.8 g of 2-(2-bromoethoxy)tetrahydropyran, 7.0 g of N-hydroxyphthalimide and 11.1 g of potassium carbonate in 100 ml of dimethylformamide was stirred at 80° C. for 2.5 hours. Ethyl acetate and water were then added to the reaction mixture to make a solution. The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, after which the resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 8.62 g of the title compound as a syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C1(C)C=CC=CC=1.O>[CH2:9]([O:16][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1

Procedure:
A mixture of 2,5-dibromopyridine, benzyl alcohol (1.3 eq), potassium hydroxide pellets (2.4 eq) and dibenzo-18-crown-6 (0.05 eq) in toluene (4 ml/mmol) was refluxed with azeotropic removal of water for 3 hours. After evaporation of the toluene, the resulting mixture was partitioned between chloroform and water. The crude product from the organic phase was recrystallized from ether-hexane to afford the 2-Benzyloxy-5-bromopyridine compound as a solid.
Reaction SMILES: [CH2:1]([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].O.[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1>COC(OC)(C)C>[CH3:12][C:11]1([CH3:16])[O:6][C@@H:2]([CH2:1][C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2757.9 %

Procedure:
Step A To a suspension of L-(−)-malic acid (Aldrich) (10.3 g, 77 mmol) in 2,2-dimethoxypropane (20 mL) was added p-toluenesulfonic acid monohydrate (0.4 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give ((S)-2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-acetic acid as a white solid (10.1 g, 75%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(C#N)c1
Yield: 24.9 %

Procedure:
If the procedure described in Preparation LXXVIII is followed starting from 0.5 g (1.4.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 0.25 g (2.1.10-3 mol) of 3-hydroxybenzonitrile and 170 mg (2.1.10-3 mol) of zinc oxide (ZnO) in 4 ml of anhydrous toluene and 4 ml of acetonitrile, 138 mg (yield: 25%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent, and precipitation in ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](CC#N)[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[CH2:18]([OH:20])[CH3:19].[OH-:21].[K+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:19][C:18]([OH:21])=[O:20])[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1cc(F)ccc1Sc1ccccc1
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1cc(F)ccc1Sc1ccccc1

Procedure:
80 g of 3-fluoro-6-(phenylthio)-phenylacetonitrile, 225 ml of ethanol, 75.5 g of potassium hydroxide and 225 ml of water are heated under reflux for 9 hours. The ethanol is subsequently evaporated off under reflux and the residue treated with water until completely dissolved, whereafter the neutral constituents are extracted with benzene. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with chloroform. The organic phase is washed with water, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 3-fluoro-6-(phenylthio)-phenylacetic acid which melts at 80°-83° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.O[CH2:21][C@H:22]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[C@@H:23]1[CH2:27][C@@H:26]([CH:28]([CH3:30])[CH3:29])[C:25](=[O:31])[O:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:28]([C@@H:26]1[CH2:27][C@@H:23]([CH:22]2[CH2:21][N@@:32]2[S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[O:24][C:25]1=[O:31])([CH3:30])[CH3:29]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 0.17 h

Procedure:
5.9 ml of a solution of diethyl azodicarboxylate in toluene (40%) (12.9 mmol) was added to a solution of 4.00 g of N-{(S)-2-hydroxy-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (1f) (10.7 mmol) and 3.38 g of triphenylphosphine (12.9 mmol) in tetrahydrofuran (100 ml) under ice-cooling over 10 minutes, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 3.40 g of the title compound (yield: 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][O:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](c2ccc(COS(C)(=O)=O)cc2)CC1
Reaction time: 8 h

Procedure:
15.4 g of trans-N-tert.butoxycarbonyl-N-methyl-4-(4-hydroxymethylphenyl)cyclohexylamine in 120 ml of methylene chloride are mixed at O° C. with 4.5 ml of methanesulphonic acid chloride and then 8.1 ml of triethylamine in 20 ml of methylene chloride are slowly added dropwise. After stirring overnight, water is added, the organic phase is washed with water, dried and concentrated by evaporation. After recrystallisation from diisopropylether at low temperature, 12.1 g of the title compound are obtained, melting point 138°-139° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=1.C1(C)C(C)=CC=CC=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.ClCCl>CN(C)C1C=CN=CC=1.O>[CH:21]1([C:24]([NH:1][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=2)=[O:25])[CH2:23][CH2:22]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1c(Br)cnc(N)c1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: O
Product: Cc1c(Br)cnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture comprising 10 g (43.1 mmol) of 2-amino-5-bromo-4-methyl-3-nitropyridine. 6.3 g of 4-dimethylaminopyridine and xylene (50 ml) was heated at 110° C. in a nitrogen atmosphere. 5 g (47.4 mmol) of cyclopropanecarbonyl chloride was dropwise added thereto, followed by further stirring at 110° C. for 2 hours. The reaction mixture was brought to room temperature, followed by the addition of dichloromethane (200 ml) and water (50 ml). The organic phase was separated and the aqueous phase was further extracted with dichloromethane (50 ml). The organic phases were combined and washed with water (50 ml). The resulting organic phase was dried over anhydrous magnesium sulfate and concentrated to give a crude crystal. It was recrystallized from chloroform/ethyl acetate to give 11.4 g of the title compound (yield 88%).
Reaction SMILES: S1C2C=CC=CC=2C(=[O:10])S1.OO.C(Cl)(Cl)Cl.[S:17]1(=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[S:18]1>FC(F)(F)C(O)=O>[S:17]1(=[O:10])(=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[S:18]1
Reactant: O=C1SS(=O)c2ccccc21
Reactant: O=c1ssc2ccccc12
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1SS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3H-1,2-Benzodithiol-3-one (39.2 g, 0.23 mole) in trifluoroacetic acid (250 mL) was added 40 mL of a 30% aqueous solution of hydrogen peroxide. Cooling was necessary to maintain the internal reaction temperature between 40°-45° C. After 30 minutes, an additional 40 mL of 30% H2O2 was added and the reaction mixture was heated to ensure an internal reaction temperature of 40°-45° C. 30 minutes later, the last portion of 30% H2O2 (40 mL) was added under the same temperature conditions and the rate of the reaction was monitored by TLC (CHCl3) until the disappearance of the slow moving sulfoxide byproduct, i.e., 3H-1,2-benzodithiol-3-one 1-oxide (90 minutes). The reaction mixture was then filtered and the filtrate was added onto 3.5 L of crushed ice. The white precipitate was filtered through a 600 mL fritted glass funnel of coarse porosity and thoroughly washed with water until the filtrate was neutral and free of peroxides. The solid material was then transferred into a 500 mL separatory funnel to which was added dichloromethane (200 mL) and a 1% solution of sodium bisulfite (100 mL). After vigorous shaking, the organic phase was decanted and washed with water (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the amorphous solid was dried under vacuum. The crude compound (20.8 g) was dissolved in boiling dichloromethane (ca. 70 mL). Hexanes (ca. 50 mL) was added, and the boiling solution was allowed to cool to ambient temperature and then kept in the refrigerator at 10° C. The crystalline material was collected by filtration, washed with cold hexanes and dried under vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]=1[O:27]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]=1[OH:27]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(C(=O)O)cc2)cc1O
Reaction time: 8 h
Yield: 93 %

Procedure:
46.6 g of the benzyl 4-(4-nitro-3-benzyloxyphenoxy)benzoate prepared as described in Example 4 (0.11 mol) are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate, and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The pale violet solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: [CH:1]([N:3]([CH2:16][C:17](=O)[CH3:18])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])=O.C([O-])(=O)C.[NH4+:24].N.C(OCC)(=O)C>C(O)(=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[N:3]1[CH:16]=[C:17]([CH3:18])[N:24]=[CH:1]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of methyl 4-[formyl-(2-oxopropyl)amino]-3-methoxybenzoate (118 g) and ammonium acetate (172 g) in acetic acid (255 mL) was heated and stirred at 140° C. for one hour. After the reaction was completed, the reaction solution was neutralized with aqueous ammonia under ice-cooling. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then filtered on a silica gel pad, and the filtrate was concentrated under reduced pressure. tert-Butyl methyl ether and heptane were added to the residue, and the precipitated solid was collected by filtration and washed with a solution of 50% tert-butyl methyl ether in heptane. The resulting solid was air-dried overnight to obtain 68.4 g of the title compound. Further, the crystallization mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 22.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=O)[O:5]C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[C@H:24]([CH3:25])[O:23]3)=[N:16]2)=[CH:11][CH:10]=1.O>CS(C)=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:23][C:4](=[O:5])[N:3]([O:2][CH3:1])[CH:24]3[CH3:25])=[N:16]2)=[CH:13][CH:14]=1
Reactant: CONC(=O)OC
Reactant: C[C@@H]1O[C@@H]1COc1ccn(-c2ccc(Cl)cc2)n1
Solvent: O
Solvent: CS(C)=O
Product: CON1C(=O)OC(COc2ccn(-c3ccc(Cl)cc3)n2)C1C
Temperature: 25 °C

Procedure:
To 1.08 g (10.0 mmol) methyl N-methoxycarbamate in 17 ml DMSO have been added with stirring at ambient temperature 1.00 g (8.9 mmol) potassium tert.-butylate. Stirring has been continued for 5 min before 2.00 g (7.56 mmol) 1-(4-chloro-phenyl)-3-[[(2R,3S)-3-methyloxiran-2-yl]methoxy]pyrazole have been added. The mixture was stirred at 90° C. for 20 h. After cooling to ambient temperature the reaction mixture was poured into 150 ml of water, extracted thrice with 30 ml ethyl acetate each, the combined extracts have been dried with sodium sulfate and the solvent removed in vacuo. The crude product (2.5 g) was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[C:4]([NH:10][CH3:11])=[N:3]1.[S:12](=[O:16])(=[O:15])([OH:14])[OH:13]>CO.[Pd]>[S:12]([O-:16])([OH:15])(=[O:14])=[O:13].[NH2:7][C:5]1[CH:6]=[N+:2]([CH3:1])[NH:3][C:4]=1[NH:10][CH3:11]
Reactant: CNc1nn(C)cc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: [Pd]
Solvent: CO
Product: CNc1[nH][n+](C)cc1N
Product: O=S(=O)([O-])O
Reaction time: 17 h

Procedure:
500 mg (3.20 mmoles) of 1-methyl-3-methylamino-4-nitropyrazol are hydrated in 50 ml absolute methanol with catalytic quantities of palladium/carbon at room temperature and 30 bar. The hydration is concluded after 17 hours, a pale orange precipitate is precipitated out of the filtrated solution when adding 314 mg (3.20 mmoles) of concentrated sulfuric acid, which precipitate is removed by suction and dried.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: NC1CCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Cyclobutylamine (0.192 g, 2.7 mmol) was added to a solution of Example 133 (0.600 g, 1.3 mmol) in DMF (1 mL). The reaction mixture was stirred at 120° C. for 4 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 3-4% methanol/chloroform) to obtain the title compound. Yield: 0.450 g, (66.6%); 1H NMR (CDCl3-d6): δ 1.80 (m, 6H, 3CH2), 1.94 (t, 3H, CH3), 2.2 (t, 1H, CH), 2.9 (s, 3H, CH3), 3.3 (s, 2H, CH2), 3.9 (s, 3H, CH3), 4.7 (s, 2H, CH2), 7.5 (s, 1H, Ar), 7.8 (s, 1H, Ar). 8.4 (s, 1H, Ar), 9.5 (s, 1H, Ar); MS: m/e (ES+) 423 (M+1).