Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]([CH2:16][CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]([CH2:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=CC(=O)OC)Nc1ccc(Cl)cc1
Reaction time: 2.5 h
Yield: 70.5 %

Procedure:
In a 300 ml-flask were placed 4-chloroaniline (25.0 g, 196 mmol), methyl 3-oxopentanoate (28.1 g, 216 mmol) and toluene (100 ml). To this solution was added p-toluenesulfonic acid monohydrate (0.19 g, 0.98 mmol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 23 kPa for 2.5 hours, while removing the water formed by refluxing by using a Dean-Stark trap. The heating was then discontinued, nitrogen leaked in, and the reaction mixture cooled. The solvent was evaporated off by using a rotary evaporator, and the residue was distilled under reduced pressure to give 33.1 g of the title compound. The yield was 70.5%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:15]1[S:16][C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1.O>CN(C=O)C>[C:24]1([C:17]2[S:16][C:15]([S:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:19][C:18]=2[C:20]([O:22][CH3:23])=[O:21])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Sc2ccccc2)sc1-c1ccccc1

Procedure:
A stirred suspension of K2CO3 (4.15 g, 30 mol) in 100 ml of DMF was treated in one portion with thiophenol (1.65 g, 15 mol). The compound of Example 2 (3.8 g, 15 mol) was then added and the mixture heated at 110° C.±5° C. for 2 days. Water was added and the mixture extracted twice with ether. The ether extracts were washed with H2O, dried over MgSO4 and concentrated in vacuo to yield a yellow oil. Bulb to bulb distillation yielded methyl 5-phenyl-2-phenylthio-4-thiazolecarboxylate, as a yellow oil at 130°-170° C./1 mm. This oil was crystallized from etherpetroleum ether mixtures to yield 1.6 g of white crystals, methyl 5-phenyl-2-phenylthio-4-thiazolecarboxylate, m.p. 67°-70° C., yield 33%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH3:13][Mg]Br.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:12])[CH3:13]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of quinoline-2-carboxaldehyde (7.85 g) in THF (100 mL) was added dropwise 1.4M methyl magnesium bromide in toluene and THF (46 mL). After total addition, the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into aqueous satured NH4Cl (500 mL), extracted with ethyl acetate (2×200 mL), washed with brine (100 mL), and dried (MgSO4). The solution was evaporated to dryness and chromatographed on flash silica gel using ethyl acetate:hexane (3:7) as eluant to yield the title product as a light orange solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O1CCCC1>CO>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc4ccccc34)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-napthalene-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesuIfonyl)-napthalene-ylmethyl-piperidine-4-carboxylic acid ethyl ester (6.3g, 13 mmol) dissolved in methanol (30 mL), 10 N sodium hydroxide (30 mL) and tetrahydrofuran (30 mL). The resulting reaction miixture was worked up as outlined in example 83. Yield 2.3 g (36%). yellow solid mp 226-228° C., MS: 440.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:67](=[O:68])[N:6]2[C:7]([C:54]([O:56]CC3C=CC([N+]([O-])=O)=CC=3)=[O:55])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:14]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([C:38](=[NH:53])[NH:39]C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[CH2:34][CH2:33]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:38]([N:35]1[CH2:36][CH2:37][N:32]([C:30]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:67](=[O:68])[N:6]4[C:7]=3[C:54]([OH:56])=[O:55])[CH2:16][NH:15]2)=[O:31])[CH2:33][CH2:34]1)(=[NH:39])[NH2:53]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=N)NC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCN(C(=N)N)CC4)C3)[C@H](C)[C@H]12
Yield: 63.8 %

Procedure:
680 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[4-(4-nitrobenzyl -oxycarbonylamidino)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 40 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and 950 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated in an atmosphere of hydrogen at 28° C. for 1 hour. At the end of this time, the catalyst was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure, to 10 ml. The resulting solution was subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 30 ml), eluted with mixtures of acetonitrile and water in proportions of 0:100, 2:98, 4:96 and 6:94, in that order. The fractions containing the desired compound were collected, concentrated by evaporation under reduced pressure, and freeze-dried to obtain 211 mg of the title compound as a powder.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CCCCCCC>CO>[O:2]1[C:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[CH:23][N:22]=[CH:21]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CO
Product: N#Cc1ccc(-c2cnco2)cc1
Yield: 97 %

Procedure:
To a solution of 4-Formyl-benzonitrile (5 g, 38.17 mmol) and tosylmethyl isocyanide (TosMIC) (from Aldrich, 8.33 g, 42 mmol) in MeOH (200 mL) was added K2CO3 (6.85 g, 49.62 mmol) and the mixture was stirred at reflux for 1 h. The solvent was then evaporated and saturated aqueous NaHCO3 was added. The resultant suspension was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4 and concentrated to leave a yellow solid. Trituration with heptane afforded a solid that was collected by filtration and dried under vacuum to give the title compound (6.3 g, 97%). m.p.=140° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])=[O:18]
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Reactant: COCCOc1ccccc1C(=O)NNC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1ccccc1C(=O)NN(C(=O)CCc1ccccc1-c1cccc(C)c1C)C(C)C
Yield: 35.8 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (110 mg, 0.44 mmoles) and 2-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (100 mg, 0.40 mmoles) in DMF (3 mL) was treated with triethylamine (0.16 mL, 1.19 mmoles), HOBT (64 mg, 0.48 mmoles) and EDCI (91 mg, 0.48 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product (70 mg, 36%). LC-MS m/e 489.39 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.O.NN.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Yield: 15.2 %

Procedure:
Concentrated sulfuric acid (45 mL) containing 5 mL of water was warmed to 60° C. and 8.6 g of N-(2-hydroximinoacetyl)anisidine was added in one portion. The stirred mixture was heated to 93° C. for 10 minutes and then allowed to cool to room temperature. The mixture was poured into 500 g of ice and extracted 3 times with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 5.1 g (65% yield) of 5-methoxyisatin as a dark red solid. 5-Methoxyisatin (5.0 g) and 30 mL of hydrazine hydrate were heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL of water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 1.1 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrazinocarbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluting with ethyl acetate:hexane (1:1) to give 0.7 g of 5-methoxy-2-oxindole as a yellow solid. The 1.1 g of 2-hydrazino-carbonylmethyl-4-anisidine was refluxed for 1 hour in 20 mL of 1N sodium hydroxide. The mixture was cooled, acidified to pH 2 with concentrated hydrochloric acid and extracted 3 times with 25 mL of ethyl acetate each time. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of 5-methoxy-2-oxindole as a yellow solid. The combined yield was 1.5 g or 33%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=C)=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.CC(C)=[O:25].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=[O:25])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:21][CH:22]=1
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(Cl)cc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(Cl)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-chlorobenzyl)-3,4-dimethyl-2-vinylbenzoate (0.17 g) in a mixed solvent of acetone (4.00 mL)-acetonitrile (4.00 mL)-water (4.00 mL) were added osmium oxide (fixed catalyst I) (0.07 g) and sodium periodate (0.58 g), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.02 g).
Reaction SMILES: N[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[S:17])=[CH:11][C:10]=2[F:29])[CH:3]=1.F[C:31]1C=CC(CC(N=C=S)=O)=CC=1>C(Cl)Cl>[NH2:5][C:6]1[CH:31]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[S:17])=[CH:11][C:10]=2[F:29])[CH:3]=[CH:2][N:7]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccc(F)cc3)cc2F)ncn1
Solvent: ClCCl
Product: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.6 %

Procedure:
4-Fluorophenylacetylchloride (Aldrich, 0.017 mL, 0.126 mmol, 2.5 eq) was added to a solution of sodium thiocyanate (0.014 g, 0.176 mmol, 3.5 eq) in ethyl acetate (1.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to afford a 2-(4-fluorophenyl)ethanoyl isothiocyanate solution (0.126 M). 4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 0.011 g, 0.050 mmol, 1.0 eq) was dissolved in CH2Cl2 (1.0 mL) and 2-(4-fluorophenyl)ethanoyl isothiocyanate (0.126 M, 0.50 mL, 0.063 mmol, 1.3 eq) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 0-6% MeOH in CHCl3) to afford the title compound (0.008 g, 38%) as a solid. 1H NMR (CD3OD) δ 7.85-7.95 (m, 1H), 7.67-7.69 (m, 1H), 7.13-7.28 (m, 4H), 6.95-7.00 (m, 2H), 6.05-6.15 (m, 1H), 5.90-5.91 (m, 1H), 3.65 (s, 2H); MS(ESI+) m/z 415 (M+H)+; HRMS(ESI+) calculated: 415.1040, found: 415.1041.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:8]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[C:5]1/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCOCCCCC=O
Reactant: O=C1CSC(=O)N1
Product: CCCCCCCCCCOCCCC/C=C1\SC(=O)NC1=O

Procedure:
TZD1c was prepared according to General Procedure A presented hereinabove, using 2,4-thiazolidinedione and 5-(decyloxy)pentanal as reactants.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].O[N:21]1[C:25]2C=[CH:27][CH:28]=[CH:29][C:24]=2N=N1.CCN=C=NCCCN(C)C.N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:21]2[CH2:27][CH2:28][CH2:29][CH2:24][CH2:25]2)=[O:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCCCC2)cc1[N+](=O)[O-]

Procedure:
2-Nitro-terephthalic acid 1-tert-butyl ester (500 mg, 1.88 mmol) in DCM (18 mL), was treated with 1-hydroxybenzotriazole (0.39 g, 2.43 mmol), EDCI (0.47 g, 2.43 mmol) and piperidine (0.24 mL, 2.43 mmol). After 3 hours the reaction was diluted with DCM (50 mL) and washed with aqueous NaHCO3 (30 mL), water (30 mL) and finally with brine. After drying over sodium sulphate and evaporation of the solvent the title compound was obtained as a colourless oil in quantitative yield. The crude was employed in the following reaction without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][C:7]1([CH3:13])[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[O:19]=[C:20]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][N:21]1[CH2:37][C:38](O)=[O:39].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][C:7]1([CH3:13])[NH:8][CH2:9][CH2:10][N:11]([C:38](=[O:39])[CH2:37][N:21]2[CH2:22][CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20]2=[O:19])[CH2:12]1
Reactant: COc1ccc(CC2(C)CNCCN2)cc1OC
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC2(C)CN(C(=O)CN3CCC(c4ccccc4)(c4ccccc4)C3=O)CCN2)cc1OC
Reaction time: 8 h

Procedure:
To 2-(3,4-dimethoxybenzyl)-2-methylpiperazine (0.052 g, 0.208 mmol; German Patent No. DE2438725), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.061 g, 0.208 mmol; Example 1C) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.079 g, 0.208 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.054 mL, 0.312 mmol) and the reaction stirred overnight. The reaction was loaded onto silica gel and the product eluted using a gradient of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane containing 7 N NH3 over 30 minutes to provide the title compound. MS (ESI+) m/z 528.2 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C1([N+]([O-])=O)C=CC=CC=1.[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].[Cl:25][C:26]1[CH:27]=[C:28]([O:33][CH3:34])[CH:29]=[C:30]([Cl:32])[CH:31]=1>CCOCC>[Cl:25][C:26]1[CH:27]=[C:28]([O:33][CH3:34])[CH:29]=[C:30]([Cl:32])[C:31]=1[C:17]([C:16]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=1[Cl:14])=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: COc1cc(Cl)c(C(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Anhydrous AlCl3 (4.5 g, 33.9 mmol) was placed in a round bottom flask and PhNO2 (150 mL) was added. At −78° C. 2,4-dichlorobenzoyl chloride (4.7 mL, 33.9 mmol) and 3,5-dichloro anisole (5.0 g, 28.2 mmol) were added. The reaction mixture was kept at the same temperature for 1 h and warmed to rt over 24 h. The reaction mixture was diluted with Et2O (50 mL) at 0° C. and quenched with 1N NaOH (˜30 mL). The reaction mixture was stirred vigorously until a white precipitate had been formed. The precipitates were filtered and washed with CH2Cl2 (50, 30, and 20 mL). The combined organic solvents were dried (Na2SO4), filtered, and concentrated under vacuum at ˜10 mmHg. Purification by silica gel chromatography (4:1, hexanes:CHCl3) to provide (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanone (8.3 g, 85%) as a white powder. 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J=8.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.37 (dd, J=8.1, 2.1 Hz, 1H), 6.95 (s, 2H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 197.6, 163.8, 142.0, 138.3, 137.7, 136.4, 130.3, 129.9, 127.8, 122.9, 118.4, 117.9, 114.6, 56.1; IR (film): 1619 cm−1, 1584, 1553, 1400, 1309; HRMS (FAB): C14H8Cl4O2 (M+Na1) calcd. 370.91761, found 370.91765.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)cc1F
Yield: 58.1 %

Procedure:
Using 0.21 g of 2,4-difluorobenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.17 g of 2-(2,4-difluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (70)).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:27])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:27])[CH:8]=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: CC(=O)Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(S(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
3.5 G. of 2-acetamido-4-phenylthio-1-nitrobenzene is dissolved in 35 ml. chloroform and treated at -25° C to -20° C with 2.5 g. 40% peracetic acid in 5 ml. methanol. The reaction mixture is allowed to warm slowly to 20°-25° C where it is held for four hours, then washed with sodium bisulfate solution and then with sodium bicarbonate solution. Evaporation of the solvent leaves 2-acetamido-4-phenylsulfinyl-1-nitrobenzene as a gum. This is treated with 20 ml. methanol and 10 ml. 5N aqueous sodium hydroxide at 20°-25° C for one hour. The mixture is diluted with water and the crude product filtered off. Recrystallization from benzene yields pure 2-amino-1-nitro-4-phenylsulfinylbenzene. 2.7 G. of 2-amino-1-nitro-4-phenylsulfinylbenzene is hydrogenated in 270 ml. methanol in the presence of 2.7 g. 5% palladized charcoal at one atmosphere pressure, until the theoretical uptake of hydrogen has occurred. The catalyst is removed by filtration and the filtrate concentrated to dryness. The residue is triturated with hot benzene, affording pure 1,2-diamino-4-phenylsulfinylbenzene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][CH2:8][C:9]1[C:10]([Cl:20])=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15]>>[Br:7][CH2:8][C:9]1[C:10]([Cl:20])=[C:11]([S:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(CBr)c1Cl
Reactant: C1COCCN1
Product: O=S(=O)(c1ccc(Cl)c(CBr)c1Cl)N1CCOCC1

Procedure:
Working analogously to Preparation VII, starting from morpholine and 3-bromomethyl-2,4-dichlorobenzenesulphonyl chloride, the expected product is obtained in the form of a yellow solid (Yield=85%) (the product contains the chloromethylated analogue in part).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1([CH3:17])[CH2:16][CH2:15]1.C(O)(=O)C>[Fe].O>[CH3:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][C:14]2([CH3:17])[CH2:15][CH2:16]2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1(C)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCC2(C)CC2)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A mixture of 0.61 g of 2,5-dimethyl-1-[(1-methylcyclopropyl)methoxy]-4-nitrobenzen e, 0.78 g of iron powder, 21 ml of acetic acid and 3 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.47 g of 2,5-dimethyl-4-[(1-methylcyclopropyl)methoxy]phenylamine.