Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([SiH:4]([CH:6]([CH3:8])[CH3:7])Cl)([CH3:3])[CH3:2].[CH2:9]([Mg]Cl)[CH:10]=[CH2:11]>C1COCC1>[CH2:11]([SiH:4]([CH:6]([CH3:8])[CH3:7])[CH:1]([CH3:3])[CH3:2])[CH:10]=[CH2:9]
Reactant: C=CC[Mg]Cl
Reactant: CC(C)[SiH](Cl)C(C)C
Solvent: C1CCOC1
Product: C=CC[SiH](C(C)C)C(C)C
Temperature: 40 °C
Yield: 86.8 %

Procedure:
Diisopropylchlorosilane (2.11 g, 14.0 mmol) was dissolved in anhydrous THF (12 mL) and treated with 1.2 equivalents of allylmagnesium chloride (8.4 mL, 2.0 M in THF, 16.8 mmol). The reaction was heated to 40° C. for 4 hours, then cooled and quenched with water (10 mL) and dilute sulfuric acid (10 mL), and extracted into pentane (2×50 mL). The organic layers were combined and washed with water (5×10 mL), then dried over MgSO4, filtered, and concentrated via rotary evaporator (carefully, product is volatile) to yield crude allyldiisopropylsilane (1.9 g). No further purification was performed.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:19][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:19][C:9]2[N:10]([CH3:22])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OC)cc3c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-7-methoxycyclopent[b]indole-2-carboxylic acid ethyl ester (10 g, 0.04 mole) in 75 ml of dimethylformamide, was added sodium hydride (1.7 g, 60% in oil, 0.043 mole). After stirring at ambient temperature for two hours, a solution of methyl iodide (2.7 ml, 0.043 mole) in dimethylformamide (10 ml) was added, and the mixture was stirred at 70° C. for five hours. After cooling, the mixture was poured into 200 ml of water, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed successively with water (2×) and a saturated NaCl solution, and then dried over anhydrous MgSO4. After filtering, the solvent was evaporated to afford a dark oil (~10 g) which was eluted on a silica gel column with dichloromethane via HPLC. The desired fractions were combined and concentrated to give the product as a thick yellow oil, 6.8 g.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.CN(C=O)C.[H-].[Na+].Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][N:16]=1>O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: Clc1nccc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cn(-c2nccc(N3CCOCC3)n2)cn1
Temperature: 120 °C
Yield: 94.3 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-1-H-imidazole (0.8 g, 4.0 mmol) in anhydrous DMF (5.0 mmol) was added NaH (60% dispersion in mineral oil, 0.176 g, 4.4 mmol) in a portionwise fashion over 10 minutes. When gas evolution had ceased, 4-(2-Chloro-pyrimidin-4-yl)-morpholine (21)(0.79 g, 4.00 mmol) was added and the mixture heated under the influence of microwave radiation (120° C., 14 min, fixed hold time, pre-stirring 10 seconds, high absorption setting). Water (14 ml) was added to the reaction mixture which caused a precipitate to form. The precipitate was removed by filtration, washed with water (10 ml) and dried in a desiccator to give the title compound (1.17 g, 94.4%) in suitably clean form to be used without any further purification. m/z (LC-MS, ESP): 310 [M+H]+, R/T=3.79 mins
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:31])[C@@H:25]([C:27]([SH:30])([CH3:29])[CH3:28])[NH2:26]>>[CH3:7][C:4]([CH3:5])([O:3][C:1]([N:8]([CH3:20])[C@H:9]([C:17]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:31])[C:27]([SH:30])([CH3:29])[CH3:28])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:2])[CH3:6]
Reactant: COC(=O)[C@H](N)C(C)(C)S
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C)C(C)(C)S

Procedure:
The title compound was synthesized by coupling Nα -Boc-(N-methyl) phenylalanine (19.0 g, 68.0 mmol) to 13.8 g (69.0 mmol) of D-penicillamine methylester hydrochloride using the procedure described above in Example 19. The title compound was obtained as a white solid (29.6 g, 99.3%).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15](O)[CH3:16])[CH:10]=1)([O-:5])=[O:4].[F:18]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C>C1COCC1.CCN(CC)CC>[F:18][CH:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][N:9]1[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[N:8]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(O)CCCCn1cc([N+](=O)[O-])cn1
Agent: F
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(F)CCCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 6-(4-nitro-pyrazol-1-yl)-hexan-2-ol (213 mg, 1.00 mmol) in THF (3.0 mL) was treated at rt with perfluoro-1-butanesulfonyl fluoride (0.36 mL, 2.00 mmol), triethylamine trihydrofluoride (0.33 mL, 2.00 mmol) and Et3N and the reaction mixture was stirred at rt overnight. Purification of the residue by FC (80:10 hept-EA) gave the title compound. TLC: rf (80:20 hept-EA)=0.28. LC-MS-conditions 02: tR=0.97 min; [M+H]+=216.20.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([OH:23])[C:20]([CH3:22])=[CH2:21])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.OS([O-])(=O)=O.[K+]>CN(C=O)C>[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:20]([CH3:22])=[CH2:21])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(C)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C(C)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
946 mg (6.28 mmol, 1.3 equivalents) of tert-butyldimethylchlorosilane is added to a solution of 1.173 g (4.83 mmol) of (S)-1-[(tert-butyldimethylsilyloxy)]-4-methyl-4-penten-3-ol 10 and 855 mg (12.56 mmol, 2.6 equivalents) of imidazole in 15.0 ml of absolute DMF. The mixture is stirred for 16 hours at room temperature. It is mixed with 50 ml of an aqueous 1 M KHSO4 solution and extracted four times with 50 ml of Et2O each. The combined ether extracts are dried on MgSO4. After the solvent is distilled off in a vacuum, the residue is flash-chromatographed by a silica gel column with pentane/Et2O (20:1). As an alternative to this aqueous working-up, the reaction mixture can be chromatographed directly. By the two variations of working-up procedure, 1.643 g (4.73 mmol, 98%) of 11 is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>CN(C)C=O>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([O:1][C:13](=[O:15])[CH3:14])[CH:3]=1)=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-dihydroxybenzaldehyde (5.0 g) in N,N-dimethylformamide (36 mL) was added 60% sodium hydride (1.45 g) under ice-cooling, followed by stirring the reaction mixture at room temperature for 10 minutes. Then, after addition of acetic anhydride (3.6 mL), the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2N aqueous hydrochloric acid solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:2 to 1:1) to give acetic acid 5-formyl-2-hydroxyphenyl ester (4.9 g).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[N:27]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=4)[N:11]3[N:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(OCC)(=O)C>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]3[N:27]=[C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=5)[N:11]4[N:10]=3)=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(F)nc4)nn23)c1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5cccc(S(C)(=O)=O)c5)n4n3)cn2)CC1
Reaction time: 16 h
Yield: 33.5 %

Procedure:
A solution of N-(6-fluoropyridin-3-yl)-5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (250 mg, 0.65 mmol) in 1-methylpiperazine (500 mg, 5 mmol) was heated at 140° C. After 16 h, the reaction mixture was diluted with ethyl acetate (100 mL). The resulting solution was washed with water, and the collected organic was concentrated. Purification by preparative thin layer chromatography afforded the desired product (101 mg). LCMS (ESI) m/z: 464.2. 1H NMR (400 MHz, CDCl3), δ: 8.69 (s, 1H), 8.30 (s, 1H), 8.16-8.14 (d, J=8 Hz, 1H), 8.03-8.01 (d, J=8 Hz, 1H), 7.81-7.67 (m, 2H), 7.50-7.45 (m, 2H), 6.97 (s, 1H), 6.68-6.64 (m 2H), 3.42-3.34 (m, 4H), 3.10 (s, 3H), 2.48-2.45 (m, 4H), 2.47 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:6]=[C:7]([N+:13]([O-])=O)[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:6]=[C:7]([NH:13][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: BrCc1ccccc1
Reactant: CCCOc1c(OC)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(NCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
trans-2-(3-Methoxy-4-propoxy-5-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran (50 mg, 0.12 mmole) and potassium carbonate (1.0 g) were suspended in 2 mL of DMF. Benzyl bromide (205.1 mg, 1.2 mmole) was added and the suspension was stirred at room temperature for 20 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to an oil that was purified by column chromatography with hexane/ethyl acetate solvent (yield 50.2 mg, 82.6%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(O)(=O)C.N1CCCCC1>>[CH3:19][O:18][C:12](=[O:17])[CH2:13][C:14]([CH:16]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:15]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
In the first step of the synthesis 2-nitro-benzaldehyde is reacted with methyl acetoacetate in the presence of a catalytic amount (0.01-0.7 mole, related to 1 mole of methyl acetoacetate) of piperidine acetate to give methyl-2-nitro-benzylidene-acetoacetate with a high yield of about 97%. This product is reacted after or without isolation with methyl-3-amino-crotonate. The yield of the second step is 87%, the total yield of both steps amounts to 84.4%. According to the disclosure of the cited Hungarian patent the thin layer chromatogram of the nifedipine thus obtained shows no by-products (Merck-type plate coated with kieselgel; developped with a 3:2:5 mixture of chloroform, acetone and petrolether).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:21]([CH2:23][C:24]([NH:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:6]([Cl:8])[CH:7]=1)=[O:25])#[N:22]
Reactant: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.3 %

Procedure:
To a solution of (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (60 mg, 0.19 mmol) in dimethylformamide (1 mL) was added cyanoacetic acid (25 mg, 0.29 mmol), hydroxybenzotriazole (39.73 mg, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (56.17 mg, 0.29 mmol) and N,N-diisopropylethyl amine (0.06 mL, 0.31 mmol) in the same order. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was poured onto water (10 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulphate, filtered and the solvent was removed under rotary evaporator. The product was purified by silica gel column chromatography using dichloromethane and methanol (1.5-2%) as eluant to yield 2-cyano-N-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]acetamide (8.7 mg, 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:25][C@H:14]23)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)ccc1N
Yield: 59 %

Procedure:
The title compound is prepared from 4-amino-3-methoxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 59% of theory; LC (method 4): tR=1.80 min; Mass spectrum (ESI+): m/z=323 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:12][CH2:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[F:16][C:14]([F:15])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:13][CH2:12][S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 36.9 %

Procedure:
To a solution of 2-mercapto-benzoic acid (0.10 g, 0.65 mmol) in acetone (30 ml) are added 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (0.16 g, 0.65 mmol) and potassium carbonate (0.27 g, 1.95 mmol) at RT. The reaction mixture is stirred at 70° C. for 2.5 h. The reaction mixture is diluted with water (20 ml), acidified with 2M hydrochloric acid and the aqueous layer is extracted with EtOAc (3×20 ml). The combined organic layers are washed with water (15 ml), brine (15 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (silica gel, 80% EtOAc/hexane) to yield 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-benzoic acid (0.08 g, 0.24 mmol, 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[ClH:18].[NH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>>[ClH:18].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=[N:19][OH:20])[CH:13]=[N:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cncc(C#Cc2ccc(F)cc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ON=Cc1cncc(C#Cc2ccc(F)cc2)c1
Yield: 50.8 %

Procedure:
Prepare in a similar manner as described in EXAMPLE 6 using 5-(4-fluorophenylethynyl)-pyridine-3-carbaldehyde (150 mg, 0.64 mmol), (prepared essentially as described in EXAMPLE 99), hydroxylamine hydrochloride (360 mg, 5.15 mmol) and potassium carbonate (440 mg, 3.22 mmol) to give the title compound (90 mg, 50%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=1>>[Cl:20][C:18]1[CH:19]=[C:14]([NH2:13])[CH:15]=[C:16]([Cl:22])[C:17]=1[O:21][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: COc1cccc2sc(Cl)nc12
Product: COc1cccc2sc(Oc3c(Cl)cc(N)cc3Cl)nc12

Procedure:
3,5-Dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenylamine was synthesized (21%) from 2-chloro-4-methoxybenzotiazole (257) and 4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described in Example 417.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.Cl[C:14]1[C:28]([F:29])=[CH:27][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[C:16]([S:30][CH2:31][CH2:32][CH3:33])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC>[CH:21]1([NH:20][C:18]([C:17]2[CH:27]=[C:28]([F:29])[C:14]([N:2]3[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3]3)=[N:15][C:16]=2[S:30][CH2:31][CH2:32][CH3:33])=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)C[C@@H]1CCCNC1
Reactant: CCCSc1nc(Cl)c(F)cc1C(=O)NC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)c(F)cc1C(=O)NC1CCCCC1
Temperature: 120 °C
Reaction time: 80 h

Procedure:
(S)-methyl 2-(piperidin-3-yl)acetate hydrochloride (263 mg, 1.36 mmol) was added to 6-chloro-N-cyclohexyl-5-fluoro-2-(propylthio)nicotinamide (500 mg, 1.51 mmol) and potassium carbonate (418 μl, 3.02 mmol) in butyronitrile (20 ml) at room temperature and under air. The resulting suspension was stirred at 120° C. for 80 hours.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[Br:22])[CH3:8].[C:24](OCC)(=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CCOCC>[CH2:28]([O:27][C:25](=[O:26])[C:24](=[O:30])[CH:11]([C:10]([O:9][CH2:7][CH3:8])=[O:23])[CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[Br:22])[CH3:29]
Reactant: CCOC(=O)CCCc1cc(OC)ccc1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(CCc1cc(OC)ccc1Br)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
Potassium t-butoxide (26.94 g) was suspended in 130 ml of anhydrous ether and cooled to 0° C. A solution of 60.24 g ethyl -4-(2-bromo-5-methoxy phenyl)butyrate and 43.84 g diethyl oxalate in 60 ml ether was added dropwise over 20 min. After 2 h at 25° C., the reaction was poured into 400 ml H2O and the aqueous layer was separated, acidified to pH 1 and extracted with ether. The ether layer was dried (MgSO4) and the solvent was evaporated to yield 71.26 g of the desired product as a colorless oil (89%). NMR (CDCl3) δ 1.25 (t, 3H), 1.4 (t, 3H), 2.25 (m, 2H), 2.75 (m, 2H), 3.78 (s, 3H), 4.0-4.5 (m, 5H), 6.64 (dd, 1H), 6.79 (d, 1H), 7.40 (d, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7](=O)[CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:3].C(O)(C)(C)C.[C:23]([S-:25])#[N:24].[K+]>O>[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7]1[NH:24][C:23](=[S:25])[N:9]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)[CH3:3]
Reactant: CCOC(=O)CC(=O)CNC1CCCCC1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)Cc1cn(C2CCCCC2)c(=S)[nH]1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
200 g (0.758 mol) 4-Cyclohexylamino-3-oxo-butyric acid ethyl ester hydrochloride were dissolved in 360 ml water and 120 ml tert-butanol and were heated to 90° C. Then 88.4 g (0.91 mol) KSCN were added and the mixture was heated for 20 s, thereby a phase separation occurred. After cooling to RT, the phases were separated and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with Brine, dried with MgSO4 and concentrated. The solid was digested in MTBE and filtered to yield 192 g (0.715 mol, 94%) of (1-Cyclohexyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-acetic acid ethyl ester as a beige solid. HPLC: tR=1.16 min (YMC J′ sphere ODS H 80 20×2.1 mm, 4 μm, A: H2O+0.05% TFA, B: MeCN, 4%→95% B in 2 min, 1 ml/min, 30° C.); Mass (ES+) (C13H20N2O2S): calculated. 268. found 269 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:4][C:3]1([CH3:18])[CH3:17].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>>[CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:19][CH:21]3[CH2:22][O:23]3)=[CH:14][CH:15]=2)[CH2:4][C:3]1([CH3:18])[CH3:17]
Reactant: CN1C(C)(C)CC(c2ccc(O)cc2)CC1(C)C
Reactant: ClCC1CO1
Product: CN1C(C)(C)CC(c2ccc(OCC3CO3)cc2)CC1(C)C

Procedure:
The title compound was prepared from 4-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-phenol and epichlorohydrin according to the procedures employed for the preparation of the compound in Step 1 of Example 2.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([Br:25])[CH:9]=1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([NH:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([Br:25])[CH:9]=1)(=[O:28])[CH3:27]
Reactant: Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 95.3 %

Procedure:
Pyridine (4.0 ml) was added dropwise to a stirred solution of 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (5.0 g), acetyl chloride (3.0 g) and dry chloroform (30 ml), causing an exothermic reaction (maximum temperature 60° C.). The reaction mixture was stirred at laboratory temperature for 2h and evaporated to dryness. The residue was dissolved in ethanol (25 ml), ammonia solution (d. 0.880; 25 ml) was added, and the solution was boiled under reflux for 1 h. The cooled reaction mixture was evaporated to dryness, dissolved in dichloromethane (100 ml), washed with dilute hydrochloric acid (3×50 ml) and water (50 ml), dried over anhydrous magnesium sulphate, filtered, and evaporated to give 5-acetamido-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (5.3 g), m.p. 180-187° C., in the form of a pale brown solid.