Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O)([O-:9])=[O:8]>>[CH:1]1([O:6][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N+:7]([O-:9])=[O:8])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: OC1CC=CC1
Product: O=[N+]([O-])c1ccccc1OC1CC=CC1

Procedure:
Cyclo-pent-3-en-1-ol was reacted with o-nitrophenol to yield 2-cyclopent-3-en-oxy nitrobenzene; which was reduced to the corresponding aniline; then reacted with N-hydromethyl-5-methyl-2-pyrrolidone to form the corresponding N-5-methyl-N-methylene-2-pyrrolidonyl derivative.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:19][CH:17]([CH2:18]2)[C:16](=[O:20])[N:15]([CH2:21][CH2:22][CH3:23])[C:14]3=[O:24])=[CH:9][CH:8]=1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:18][CH:17]([CH2:19]2)[C:16](=[O:20])[N:15]([CH2:21][CH2:22][CH3:23])[C:14]3=[O:24])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCN1C(=O)C2CC(c3ccc(NS(C)(=O)=O)cc3)(C2)C1=O
Reaction time: 5 h

Procedure:
A solution of 0.31 ml of methanesulphonic acid chloride in 3 ml of methylene chloride is added at room temperature to a solution of 1.03 g of 1-(4-aminophenyl)-3-n-propyl-3azabicyclo[3.1.1]heptane-2,4-dione and 24 mg of 4-dimethylaminopyridine in 10 ml of pyridine. After stirring for 5 hours, 50 ml of water are added, and the mixture is left to stand overnight at 0°-5°. Extraction is carried out with methylene chloride, and the organic phase is washed in succession with water, cold 2N hydrochloric acid, water, semi-saturated bicarbonate solution and water. After drying over magnesium sulphate, the mixture is filtered and concentrated by evaporation, and the residue is recrystallised from methanol. The title compound is obtained in the form of white crystals having a melting point of 159°-160°. Rf (hexane/ethyl acetate 1:1)=0.15.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.O.[NH2:13][NH2:14]>C(O)(C)C>[NH:13]([C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1)[NH2:14]
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: Cn1c(NN)cc(=O)n(C)c1=O

Procedure:
A mixture of Step 1 intermediate (17 g, 97.34 mmol) and hydrazine hydrate (119 ml) in isopropyl alcohol (280 ml) were refluxed for 1 h. The excess of solvent was removed under reduced pressure, solid obtained was filtered, washed with methanol (25 ml) and dried to obtain 8.1 g of the product as white solid; 1H NMR (300 MHz, DMSO-d6): δ 3.09 (s, 3H), 3.21 (s, 3H), 4.37 (br s, 2H), 5.10 (s, 1H), 8.02 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4](SC)[N:3]=1.O[O:20][S:21]([O-:23])=O.[K+].[C:25]([O-])(O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:15])([F:16])[F:14])[N:5]=[C:4]([S:21]([CH3:25])(=[O:23])=[O:20])[N:3]=1
Reactant: CSc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-chloro-2-(methylthio)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]pyrimidine (1.45 g, 4.87 mmol) in CH3OH (15 mL) was cooled in an ice bath and treated slowly with a premixed solution of oxone (3.89 g, 6.33 mmol) in water (5 mL). The reaction was let stir at room temperature overnight. The reaction was diluted with water (20 mL) followed by saturated NaHCO3 (30 mL). The mixture was extracted with EtOAc (3×50 mL). The organic was combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated to afford the crude title compound (1.55 g) as a yellowish oil. LC-MS (ES) m/z=330 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(O)CCC>[ClH:15].[NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:25]([O:24][CH3:23])[CH:26]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Reactant: COc1cccc(N)c1
Solvent: CCCCO
Product: COc1cccc(Nc2nnc(Cc3ccncc3)c3ccc(NC(C)=O)cc23)c1
Product: Cl

Procedure:
By analogy with 25,300 mg (0.96 mmol) 7-acetamino-1-chloro-4-(4-pyridylmethyl)phthalazine is reacted in 3.9 ml 1-butanol with 321 μl (2.88 mmol) 3-methoxyaniline to obtain title compound: m.p.: 156-159° C.; HPLC: tRet(Grad5-40)=11.0; FAB MS (M+H)+=400.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([OH:35])=[C:16]2[C:32](=[O:33])[N:20]3[C@@H:21]([CH3:31])[CH2:22][CH2:23][N:24]([CH:25]4[CH2:30][CH2:29][S:28][CH2:27][CH2:26]4)[C@@H:19]3[CH2:18][N:17]2[CH:34]=1)=[O:12].N[C@@H](C)CCN[CH:42]1[CH2:47][CH2:46]S[CH2:44][CH2:43]1.[C:49]([OH:52])(=O)[CH3:50].[Cl:53]CCl>>[ClH:53].[ClH:53].[NH2:20][C@@H:21]([CH3:31])[CH2:22][CH2:23][NH:24][CH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1.[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([OH:35])=[C:16]2[C:32](=[O:33])[N:20]3[C@@H:21]([CH3:31])[CH2:22][CH2:23][N:24]([CH:25]4[CH2:30][CH2:29][S:28][CH2:27][CH2:26]4)[C@@H:19]3[CH2:18][N:17]2[CH:34]=1)=[O:12].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([O:52][CH2:49][C:50]2[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=2)=[C:16]2[C:32](=[O:33])[N:20]3[C@@H:21]([CH3:31])[CH2:22][CH2:23][N:24]([CH:25]4[CH2:26][CH2:27][S:28][CH2:29][CH2:30]4)[C@@H:19]3[CH2:18][N:17]2[CH:34]=1)=[O:12]
Reactant: CC(=O)O
Reactant: ClCCl
Agent: C[C@H](N)CCNC1CCSCC1
Agent: C[C@H]1CCN(C2CCSCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Product: C[C@H]1CCN(C2CCSCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCc4ccccc4)c3C(=O)N12
Product: Cl
Yield: 54 %

Procedure:
[(3S)-3-Aminobutyl]tetrahydro-2H-thiopyran-4-ylamine dihydrochloride was prepared in a similar manner as described in example Z-47. 1H NMR (400 MHz, CDCl3/CD3OD) δ 1.21 (d, J=6.4 Hz, 3H), 1.65-1.75 (m, 2H), 1.90-2.10 (m, 2H), 2.35 (m, 2H), 2.56-2.61 (m, 4H), 2.92-2.98 (m, 3H), 3,273.31 (m, 1H), 8.05 (br, <1H), 8.90 (br, <1H). b) (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2, 16a (80 mg, 0.17 mmol) and free based [(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine (108 mg, 0.58 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (56 mg, 54%) as a film. This material was debenzylated in a second step to in a manner similar to Z-26 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (56 mg, >100%) as an off-white solid, 1H NMR (4.00 MHz, CDCl3) δ 1.30 (d, J=6.8 Hz, 3H), 1.54-1.58 (m, 1H), 1.72-1.82 (m, 3H), 1.97-2.11 (m, 2H), 2.60-2.76 (5H), 2.86 (m, 2H), 4.17-4.30 (m, 2H), 4.62-4.66 (m, 3H), 4.92-4.96 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 1H), 8.31 (s, 1H), 10.46 (s, 1H), 12.48 (s, 1H); ES+ MS: 519 (M+1).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]3[C:30]([N:31](S(C)(=O)=O)[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][N:28]=[C:27]([N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[N:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl>CO.C1COCC1>[N:1]1([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]3[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][N:28]=[C:27]([N:40]([CH2:41][CH3:42])[CH2:43][CH3:44])[N:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)c1ncc(N(S(C)(=O)=O)S(C)(=O)=O)c(N[C@@H](Cc2ccc(OC(=O)N3CCCC3)cc2)C(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)c1ncc(NS(C)(=O)=O)c(N[C@@H](Cc2ccc(OC(=O)N3CCCC3)cc2)C(=O)OC(C)(C)C)n1
Temperature: 40 °C
Yield: 85.7 %

Procedure:
Compound 10 (2.2 g, 3.4 mmol) was dissolved in methanol (5 mL) and THF (5 mL). 1.0 M K2CO3 (10 mL) was added and the reaction mixture was heated at 40° C. for 96 hours. The reaction mixture was acidified to pH 3 with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 1.68 g (86%) product as a beige foam, compound 11. The crude material was used without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:28][C:29]([NH2:31])=[O:30])([O-:3])=[O:2].Cl.Cl[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:28][C:29]([NH2:31])=[O:30])=[C:9]([NH:8][CH2:7][C:6]4[CH:32]=[CH:33][CH:34]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:14]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1)[CH3:37]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN1CCN(c2ccc(Nc3cc(NCc4cccc([N+](=O)[O-])c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
40 mg of 4-[(3-nitrobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 224) was dissolved in 0.3 mL of N,N-dimethylformamide, to which 18.5 mg of 2-chloro-N,N-diethylethylamine hydrochloride and 25 mg of potassium carbonate were added, and stirred at room temperature for 3 hours. Water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 43 mg (88%) of the title compound as an orange crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1>CO.C(N1CCC(=O)CC1)(=O)C1C=CC=CC=1>[C:11]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:9][C:8](=[O:10])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCN(C(=O)c3ccccc3)CC2)Oc2ccccc21
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of 2′-hydroxyacetophenone (5, 5.88 mL, 48.85 mmol), 1-benzoyl-4-piperidone (6, 10 g, 49 mmol), and pyrrolidine (4.1 mL, 49 mmol) in 55 mL of methanol was heated in an oil bath at 65° C. After ˜18 hours the oil bath was removed and the solution was allowed to cool to room temperature. Additional 1-benzoyl-4-piperidone (6, 100 mg, 0.5 mmol) was added and heating at 65° C. was resumed. After an additional ˜2.5 hours the oil bath was removed and the solution was allowed to cool to room temperature. This mixture was concentrated under reduced pressure on a rotary evaporator followed by high vacuum to give a viscous, orange oil. This oil was triturated with diethyl ether to provide a solid that was collected by vacuum filtration, washed with diethyl ether, and dried in vacuo at room temperature to afford 1′-benzoylspiro[chroman-2,4′-piperidin]-4-one (7) as an off-white solid (14.72 g, 93.8% yield). The filtrate was evaporated to dryness, triturated with diethyl ether, filtered, washed with diethyl ether, and dried in vacuo at room temperature to afford additional compound 7 as a pale tan solid (0.54 g, 3.7% yield). Both samples were homogeneous by TLC (silica gel, 1.5% methanol in dichloromethane, UV visualization; Rf (7)=0.15−0.2).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@:16]1([CH2:20][C:21]#[CH:22])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@:16]1([CH2:20][C:21]#[CH:22])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:26])[CH3:25]
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reaction time: 16 h

Procedure:
To a solution of 500 mg of 17β-hydroxy-10-(2-propynyl)estr-4-en-3-one in 4 ml of pyridine at 25° C. is added 4 ml of acetic anhydride and the mixture is allowed to stand at room temperature for 16 hours. It is then concentrated under reduced pressure, the residue is diluted with ether and the ether solution is washed with 1 N hydrochloric acid and with aqueous sodium bicarbonate and then dried and concentrated. The resultant residue is recrystallized from ethyl acetate-hexane to give 17β-acetoxy-10-(2-propynyl)estr-4-en-3-one. This compound has the following structural formula ##STR10##
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>ClCCl.O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)O)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 12 h

Procedure:
1.3 g tert-butyl 1-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-4-carboxylate are dissolved in 20 ml dichloromethane, combined with 1.04 ml of a 4 M solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hours. A further 2 ml of a 4 M solution of hydrogen chloride in 1,4-dioxane is added and the mixture is stirred for a further 24 hours. The solvents are eliminated in vacuo and the residue is taken up twice in dichloromethane and this is then eliminated in vacuo. The product thus obtained is further reacted directly.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[CH:23][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[O:32][C:33]=3[CH3:34])=[CH:23][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A mixture of ethyl [1-benzyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (731 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-benzyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetic acid (580 mg, yield 84%), which was then recrystallized from acetone-hexane. melting point: 91–92° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([NH:17][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH2:16][CH2:15]1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-methyl-3 nitrobenzoyl chloride (20 g) in methylene chloride (200 mL) at 0° C. was added a mixture of cyclopropylamine (7.62 mL) and triethylamine (28 mL). The mixture was allowed to warm to room temperature and stirred for a further 16 hours. The reaction mixture was evaporated in vacuo and a saturated aqueous solution of sodium bicarbonate was added. The precipitated solid was filtered off and washed with isohexane and dried (magnesium sulphate) to give N-cyclopropyl-4-methyl-3-nitrobenzamide as a colourless solid (22.9 g); NMR Spectrum: (DMSOd6) 0.60 (m, 2H), 0.72 (m, 2H), 2.56 (s, 3H), 2.87 (m, 1H), 7.60 (d, 1H), 8.06 (m, 1H), 8.41 (d, 1H), 8.67 (d, 1H); Mass Spectrum: M+H+ 221. B) A suspension of N-cyclopropyl-4-methyl-3-nitrobenzamide (22.92 g) and 10% palladium on carbon (2 g) in absolute alcohol (500 mL) was agitated under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate evaporated to dryness to give the title compound as a colourless solid (17.1 g); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.65 (m, 2H), 2.07 (s, 3H), 2.80 (m, 1H), 6.92 (m, 2H), 7.06 (d, 1H), 8.09 (d, 1H); Mass Spectrum: M+H+ 191.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]([CH3:67])[C:57](=[O:66])[O:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>C(OC(C)C)(=O)C.CCOC(C)=O>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][C:11]1([C:14](=[O:15])[NH:65][C:61]2[CH:62]=[CH:63][CH:64]=[C:59]([O:58][C:57](=[O:66])[N:56]([CH3:55])[CH3:67])[CH:60]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CN(C)CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
1-(tert-Butoxycarbonyl)-4-(2-(dimethylamino)ethyl)piperidine-4-carboxylic acid from step B (100 mg, 0.33 mmol), HATU (175 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.116 mL, 0.67 mmol) were stirred in isopropyl acetate for 10 minutes. 3-aminophenyl dimethylcarbamate (90 mg, 0.5 mmol) was added, and the reaction was stirred at 85° C. for 2 hours, cooled to room temperature, stirred overnight, and then diluted with EtOAc, washed with sat. aq. Na2CO3 and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum, to give the title compound as a viscous oil. MS (ES+) [M+H]+=463.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=1)=[O:4].[O-:12][Mn](=O)(=O)=O.[K+].OS([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COC(=O)c1cc(C=O)c[nH]1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) in acetone/water (50 mL, 1:1) was added a solution of KMnO4 in acetone/water (70 mL, 1:1) dropwise within one hour. The mixture was stirred for 3 h at RT whereupon it was poured into a solution of NaHSO3 (10% in 1 N HCl, 100 mL). The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and extracted with 2N aqueous K2CO3 solution. The basic aqueous phase was acidified with 2N HCl and extracted with ethyl acetate The combined organic phases were dried (MgSO4) and concentrated in vacuo to provide 1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (530 mg) which was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])C.C(O)C.[F:13][C:14](Cl)(Cl)[S:15]Cl.[CH:19]([Cl:22])(Cl)[Cl:20]>>[C:4]1([C:1]([C:14]([F:13])([CH:19]([Cl:22])[Cl:20])[SH:15])=[O:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: FC(Cl)(Cl)SCl
Reactant: CC(=O)c1ccccc1
Reactant: ClC(Cl)Cl
Solvent: CCO
Product: O=C(c1ccccc1)C(F)(S)C(Cl)Cl

Procedure:
240 g (2 moles) of acetophenone were dissolved in 300 ml of chloroform and, after addition of 3 ml of ethanol and 109 g (0.64 mole) of fluorodichloromethanesulphenyl chloride, the mixture was heated to the reflux temperature. A further 400 g (2.36 moles) of fluorodichloromethane-sulphenyl chloride were added dropwise in the course of 30 minutes and the mixture was then heated under reflux for 5 hours. For subsequent working up, the reaction mixture was subjected to fractional distillation under reduced pressure. After first runnings of unchanged starting material, 126 g of fluorodichloromethyl-mercaptomethyl phenyl ketone were obtained in the form of a liquid of boiling point 128° C./0.4 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].Br[C:32]1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C(Cl)C=1.CC1C=C(N)C=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH3:32])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (2.82 mmol) and 3-methyl-phenylamine (3.10 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 5:95 to 30:70 as the eluent to afford the title compound.