Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:22])=[C:14]([N+:19]([O-])=O)[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1>C(O)C.[C].[Pd]>[NH2:19][C:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]2[O:3][C:2]([CH3:23])([CH3:1])[CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]=2[C:13]=1[CH3:22]
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C)C2c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Yield: 73.9 %

Procedure:
2,2,4,6,7-Pentamethyl-5-nitro-3-phenyl-2,3-dihydrobenzofuran (2.0 g, 6.4 mmol) was dissolved in ethanol (15 ml) and the solution was subjected to catalytic reduction using 5% palladium carbon (2.0 g) as a catalyst. After the catalyst was filtered off, the filtrate was concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether) and then crystallized from hexane to obtain the desired compound (1.33 g, yield: 73.6%), m.p. 131°-132° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH:11]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][CH:20]=1)[CH:12]([CH3:14])[CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+].O>ClCCl.C(O)C>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH:11]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:19][CH:20]=1)[CH:12]([CH3:13])[CH3:14])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(NC(=O)OC(C)(C)C)nc1)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)O)C(c1ccc(NC(=O)OC(C)(C)C)nc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propyl]-malonic acid diethyl ester (1.569 g, 3.84 mmol) in a mixture of dichloromethane (6 mL) and ethanol (12 mL, 95%) at 0° C. a solution of potassium hydroxide (0.272 g, 85%, 4.2 mmol) in ethanol (6 mL, 95%) was added dropwise over 40 min. After additional 1 h stirring the mixture was allowed to warm up to room temperature and stirring was continued for 18 h. Then water (30 mL) and dichloromethane (30 mL) were added, and after 3 min stirring the layers were separated. The organic was extracted once with water and the combined aqueous were washed once with ether. Then an aqueous solution of citric acid (10%) was added to adjust the pH to 4, and the solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulphate. After evaporation of the solvent crude 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propyl]-malonic acid monoethyl ester (0.94 g, 64%) was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[S:21]1[C:25]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:24][N:23]=[CH:22]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:25]3[S:21][CH:22]=[N:23][CH:24]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(-c2cncs2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2cncs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(thiazol-5-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 408.98 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]([Cl:22])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC1(c2ccc(F)cc2)CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCC1(c2ccc(F)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(1-(4-fluorophenyl)cyclohexyl)propanoic acid (Preparation 42A, 209 mg, 0.835 mmol) in dichloromethane (3 mL) at 0° C. was added oxalyl chloride (0.146 mL, 1.670 mmol) followed by a couple of drops of N,N-dimethylformamide, and the mixture was stirred at the same temperature for 20 mins and warmed up to room temperature. The volatiles were evaporated off and the residue was used for next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)([C:5]1[CH:6]=[N:7][C:8]([O:11][CH:12]([F:14])[F:13])=[CH:9][CH:10]=1)[CH2:3][OH:4].Cl[CH2:23][C:24](Cl)=[O:25].C([O-])(C)(C)C.[K+]>C(O)(C)(C)C>[Br:21][C:17]1[CH:16]=[C:15]([C:2]2([C:5]3[CH:6]=[N:7][C:8]([O:11][CH:12]([F:14])[F:13])=[CH:9][CH:10]=3)[NH:1][C:24](=[O:25])[CH2:23][O:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CO)(c1ccc(OC(F)F)nc1)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1COCC(c2ccc(OC(F)F)nc2)(c2cccc(Br)c2)N1

Procedure:
In close analogy to the reaction sequence described for the preparation of intermediate X-1, the acylation of the (RS)-2-amino-2-(3-bromo-phenyl)-2-(6-difluoromethoxy-pyridin-3-yl)-ethanol with chloroacetylchloride followed by cyclisation with tert-butanol and potassium tert-butanolate yielded the (RS)-5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-morpholin-3-one as a light yellow solid (1.6 g, 91% of theory). MS (ISP): m/z=400.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:26]([CH3:28])[CH3:27])[C:10]([NH:12][C@@H:13]([CH3:25])[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22](O)=[O:23])[NH:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:30][O:31][C:32](=[O:51])[C:33]([CH3:50])([CH3:49])/[CH:34]=[CH:35]/[C:36]1[CH:45]=[C:44]2[C:39]([CH:40]=[CH:41][C:42]([C@H:46]([NH2:48])[CH3:47])=[N:43]2)=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:30][O:31][C:32](=[O:51])[C:33]([CH3:50])([CH3:49])/[CH:34]=[CH:35]/[C:36]1[CH:45]=[C:44]2[C:39]([CH:40]=[CH:41][C:42]([C@H:46]([NH:48][C:22]([C@@H:18]3[CH2:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:26]([CH3:28])[CH3:27])[CH3:25])[NH:17]3)=[O:23])[CH3:47])=[N:43]2)=[CH:38][CH:37]=1
Reactant: COC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)N)nc2c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)NC(=O)[C@@H]3CCCN(C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A cooled (0° C.) solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (696 mg, 1.74 mmol) and crude (E)-4-[2-((R)-1-amino-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acid methyl ester hydrochloride in acetonitrile (20 mL) was subsequently treated with N,N-diisopropylethylamine (1.52 mL, 8.71 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (861 mg, 2.26 mmol). After stirring at room temperature for 2 h, the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate, and subsequently washed with saturated ammonium chloride solution and sodium hydrogen carbonate solution. The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 1:1 to afford the title compound (868 mg, 73%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 0.82-0.97 (m, 6H), 1.36 (d, J=6.9 Hz, 3H), 1.45 (s, 9H), 1.48 (s, 6H), 1.61 (d, J=6.9 Hz, 3H), 1.66-1.76 (m, 2H), 1.83-2.12 (m, 3H), 2.78-2.92 (m, 1H), 3.52-3.61 (m, 1H), 3.74 (s, 3H), 3.82-3.95 (m, 1H), 4.25-4.35 (m, 1H), 5.23 (q, J=6.9 Hz, 1H), 5.36 (q, J=6.9 Hz, 1H), 6.36-6.51 (m, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.99 (s, 1H), 8.25 (d, J=8.5 Hz, 1H). LCMS (m/z) 681.4 [M+H], Tr=2.62 min.
Reaction SMILES: [CH:1]1([C:6]2[N:10]3[C:11]([CH2:21][CH3:22])=[N:12][N:13]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:9]3=[N:8][C:7]=2[OH:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([N:26]1[C:30]([CH2:31]O)=[N:29][CH:28]=[N:27]1)[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([C:6]2[N:10]3[C:11]([CH2:21][CH3:22])=[N:12][N:13]=[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:8][C:7]=2[O:23][CH2:31][C:30]2[N:26]([CH2:24][CH3:25])[N:27]=[CH:28][N:29]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nnc(-c2ccccc2)c2nc(O)c(C3CCCC3)n12
Reactant: CCn1ncnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nnc(-c2ccccc2)c2nc(OCc3ncnn3CC)c(C3CCCC3)n12

Procedure:
To a solution of the product of Example 12 a) (150 mg, 0.48 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (93 mg, 0.73 mmol) in tetrahydrofuran (5 ml) at 0° C. was added triphenylphosphine (192 mg, 0.73 mmol) followed by diethyl azodicarboxylate (110 μl, 0.73 mmol) dropwise with stirring. After 2 hours the tetrahydrofuran was evaporated in vacuo and the residue dissolved in dichloromethane (50 ml) and washed with water (2×20 ml). The organic phase was separated, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by prep. TLC (SiO2; 30% ethyl acetate in isohexane), and the product recrystallised from ether/isohexane to afford 35 mg (17%) as a white solid. δH (400 MHz; CDCl3) 1.43 (3H, t, J 7.2), 1.57 (3H, t, J 7.2), 1.71 (2H, m), 1.84 (2H, m), 2.02 (4H, m), 3.37 (2H, q, J 7.3), 3.66 (1H, quin, J 8.7), 4.30 (2H, q, J 7.2), 5.66 (2H, s), 7.53 (3H, m), 7.92 (1H, s), 8.54 (2H, m); m/z (ES+) 418 (M++H, 100%).
Reaction SMILES: Br[CH:2]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][NH2:28]>C(#N)C>[C:6]([O:5][C:3](=[O:4])[CH:2]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][NH2:28])([CH3:9])([CH3:8])[CH3:7]
Reactant: NCCNCCN
Reactant: CC(C)(C)OC(=O)C(Br)COCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(COCc1ccc([N+](=O)[O-])cc1)NCCNCCN
Temperature: 35 °C
Yield: 79.8 %

Procedure:
A solution of 14 g of t-butyl 2-bromo-3-[(4-nitrophenyl)methoxy]propanoate (prepared according to the procedure described by P. L. Rings et al., Synth. Commun., 1993, 23, 2639) (0.0389 mol), in 30 ml of acetonitrile was added to a solution of 20 g of diethylenetriamine (0.19 mol) in 20 ml of acetonitrile kept at 0°-5° C. and under inert atmosphere. The solution was then heated to 35° C. for 4 h. The solvent was evaporated under vacuum and 100 ml of a NaCl saturated solution were added to the residue. The solution was extracted with Et2O; the organic phase was washed with H2O, dried and concentrated under vacuum to obtain 12 g of the desired product (0.031 mol).
Reaction SMILES: [C:1]1([C:9]#[N:10])([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[NH2:8][CH2:7][C:1]1([CH2:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(C#N)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC1(CN)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclohexane-1,1-dicarbonitrile (20.0 g) was taken up in dry Et2O (70 mL). This mixture was added dropwise to a suspension of LiAlH4 (17.0 g) in dry Et2O (250 mL) cooled in an ice bath. The mixture was stirred overnight at room temperature, cooled in an ice bath, and quenched by adding H2O (17.0 mL), 2M aqueous NaOH (34.0 mL) and again H2O (17 mL). The suspension was filtered, the filter cake was washed with Et2O, and the combined filtrates were evaporated to dryness yielding 20.8 g of a clear, colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.05-1.55 (m, 14H), 2.61 (s, 4H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])(=O)=O>CN(C)C=O>[F:36][C:31]([F:37])([C:32]([F:35])([F:34])[F:33])[CH2:30][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(OC(F)(F)F)cc1)CC(F)(F)C(F)(F)F
Yield: 26 %

Procedure:
Using 0.3 g of (4-(trifluoromethoxy)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.073 g of cesium carbonate, and 0.35 g of 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(2,2,3,3,3-pentafluoropropyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (5)).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[C:11]([O:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][CH2:27][OH:28])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:11]([O:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]\[CH2:27][OH:28])[CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COc1cccc(C#CCO)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CC(C)(C)OC(=O)COc1cccc(/C=C\CO)c1
Reaction time: 1 h
Yield: 76 %

Procedure:
Quinoline (54 μL) and a Lindlar catalyst (54 mg) were added to a stirred solution of [3-(3-hydroxyprop-1-ynyl)phenoxy]acetic acid tert-butyl ester (547 mg, 2.09 mmol) in methanol (4.3 mL) under a nitrogen atmosphere. The mixture was stirred for 1 hour in a balloon filled with hydrogen, filtered, and the filtrate was taken to dryness. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate, dissolved in diethyl ether, and washed with 2 N hydrochloric acid (10 mL) and 10% sodium bicarbonate, dried over sodium sulfate, and concentrated to give cis-[3-(3-hydroxypropenyl)phenoxy]acetic acid tert-butyl ester as a colorless oil (420 mg, 76%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O>[S:17]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
99.26 g of anthranilic acid was added to 830 g of water, the resulting mixture was heated at 75° C. and 165.3 g of p-toluenesulfonyl chloride was added thereto over 30 minutes with stirring. 495 g of 28% aqueous solution of sodium hydroxide was added dropwise and the mixture was stirred at 80° C. for one hour. The reaction mixture was added dropwise to a mixed solution of 360 g of 35% hydrochloric acid and 270 g of water at 70 to 80° C. and stirred for one hour. After cooling to 30° C., the mixture was filtered, the resulting crystals were washed with water, and the wet crystals were heated and solved in 750 g of 1-propanol to obtain a solution. After cooling to a room temperature, the solution was filtered, the resulting crystals were washed with 1-propanol, and dried under a reduced pressure to obtain 175 g of N-tosyl anthranilic acid.
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]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:40]=1[CH2:49][C:50]([O:52][CH3:53])=[O:51])#[CH:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:53][O:52][C:50](=[O:51])[CH2:49][C:40]1[CH:41]=[C:42]([C:45]([F:47])([F:46])[F:48])[CH:43]=[CH:44][C:39]=1[C:37]#[C:38][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]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccc(C(F)(F)F)cc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Product: COC(=O)Cc1cc(C(F)(F)F)ccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.300 g, 0.656 mmol), PdCl2(PPh3)2 (0.046 g, 0.066 mmol), t-Bu3PH.BF4 (0.019 g, 0.066 mmol), CuI (0.013 g, 0.022 mmol) and methyl 2-(2-ethynyl-5-(trifluoromethyl)phenyl)acetate (A105) (0.191 g, 0.657 mmol) in dry degassed DMF (4 mL) and Et3N (4 mL) was heated at 120° C. for 20 minutes under nitrogen. The volatiles were evaporated under reduced pressure and the residue adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A106 as a yellow solid (0.196 g, 45%); 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.60-7.53 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 4.25 (s, 2H), 3.99 (s, 2H), 3.72 (s, 3H), 2.80 (t, J=11.9 Hz, 2H), 2.64 (m, 1H), 1.82 (d, J=12.8 Hz, 2H), 1.68-1.53 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.109 min; m/z 663.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:11][C:12](Cl)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:12](=[O:13])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C(Cl)Cc1cccc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNC(=O)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 16.3 g of 1-naphthyl-acetic acid chloride in 80 ml of chloroform was added at +10° C. to a solution cooled to +10° C. of 15 g of N-(tert-butoxycarbonyl)-1,4-diamino butane, 100 ml of chloroform and 14 ml of triethylamine and after one hour of stirring at ambient temperature, the mixture was concentrated to dryness under reduced pressure. The residue was taken up in water, separated and dried under reduced pressure at 50° C. to obtain 27.8 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9](Cl)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1.C([O:21][C:22]([C:24]1[N:25]=[CH:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:28]=1[NH2:29])=O)C>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22](=[O:21])[C:24]3[N:25]=[CH:26][N:27]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:28]=3[N:29]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn(-c2ccccc2)c1N
Reactant: ClC(=Nc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Br)cc1
Temperature: 120 °C
Yield: 36 %

Procedure:
To a solution of N-(4-bromo-phenyl)-2,4-dichloro-benzimidoyl chloride (0.22 mmol) and 5-amino-1-phenyl-1H-imidazole-4-carboxylic acid ethyl ester (65 mg, 0.27 mmol) in 1,2-dichloroethane is added titanium tetrachloride (98 μL, 0.89 mmol) dropwise at room temperature. After addition is completed, the reaction mixture is heated at 120° C. for 18 hours. After the reaction is quenched with water and the aqueous layer is extracted with ethyl acetate. The organic solvents are combined and dried over magnesium sulfate. Filtration and concentration provide a crude product which is purified by column chromatography gave a white solid as product (41 mg, three steps yield 36%). 1H NMR (CDCl3) δ(ppm) 8.04 (s, 1H), 7.58 (d, 2H), 7.47 (t, 2H), 7.38 (m, 3H), 7.22 (d, 1H), 7.15 (b, 1H), 7.07 (m, 2H), 6.91 (b, 1H); HPLC-MS calculated for C23H13BrCl2N40 (M+H+): 511.0. Found: 511.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.[H-].[Na+]>>[Cl:9][C:10]1[N:15]=[C:14]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1ccc(S)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(Sc2ccnc(Cl)n2)cc1

Procedure:
The 2-chloro-4-(4-methylphenylsulphanyl)pyrimidine was prepared in a similar manner to the analogous starting material of Example 1, from p-thiocresol (838 mg, 6.71 mmol), 2,4-dichloropyrimidine (1.0 g, 6.71 mmol) and sodium hydride [60% dispersion in oil] (295 mg, 7.4 mmol), m.p. 80-81°. δH (CDCl3) 8.15 (1H, d, J 5.4 Hz), 7.46 (2H, d, J 8.0 Hz), 7.30 (2H, d, J 8.0 Hz), 6.59 (1H, d, J 5.4 Hz) and 2.43 (3H, s).
Reaction SMILES: [CH:1]([CH:3]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])=[O:2].[H-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1>O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:7]2[CH2:8][CH2:9][N:5]([CH:4]=[CH:3][CH:1]=[O:2])[C:6]2=[N:10][N+:11]([O-:13])=[O:12])=[CH:24][N:23]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=CC=CN1CCNC1=N[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
A mixture comprising 3.0 g of 1-(formylvinyl)-2-nitroiminoimidazolidine, 0.7 g of sodium hydride and 30 ml of DMF was stirred at 40° C. for 15 minutes. After this was cooled to room temperature, 3.2 g of 2-chloro-5-chloromethylpyridine was added thereto and stirred at 60° C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate) to give 2.3 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-formylvinyl)imidazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:18][C:22]([CH3:28])([CH3:27])[C:23](=[O:24])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CC(C)(Br)C(=O)C#N
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.6 g of 1-{3-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone in 100 ml dry THF was stirred at 0° C. for 20 minutes in the presence of 60% oil dispersion of sodium hydride (1.5 g), which was followed by dropwise addition of α-bromoisobutyryl cyanide (3.0 ml) diluted in 50 ml THF. The reaction solution was allowed to warm slowly to room temperature and was stirred overnight. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=8:1) to yield 3.2 g of 5-{3-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.52 (s, 6H), 2.45 (s, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.25 (m, 3H), 7.32 (m, 2H), 7.87 (dd, J=8.4, 1.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H). IR (cm−1): 1694, 1613, 1592, 1389, 1252, 1145, 1128.