Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:6]1)=[N+:2]=[N-:3].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[CH2:35][NH2:36].C(N(CC)C(C)C)(C)C>C(O)CCC>[N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:36][CH2:35][C:28]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH3:25])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 80 °C

Procedure:
A solution of 9-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-9H-purine (1.29 g, 3.69 mmol) and (2,4-dimethoxyphenyl)methanamine (0.71 mL, 4.7 mmol) in 1-butanol (10 mL) was treated with N,N-diisopropylethylamine (0.93 mL, 5.3 mmol) and heated at 80° C. for 16.5 h; HPLC/LC MS indicated conversion to the desired product. The reaction mixture was allowed to cool to rt and the volatiles were removed under the flow of air to afford a brown-orange paste. Purification by column chromatography (2×8 cm silica; 0-10% acetone/CH2Cl2) afforded the title compound (1.72 g, 97%) as a yellow-orange foam/oil: MS (ESI+) for C23H28N8O4 m/z 481.2 (M+H)+; HPLC purity >95 area %.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:32](=[CH:33][CH:34]=[CH:35][C:28]=2[Cl:27])[O:36]1)=[O:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C=O
Reactant: O=Cc1c(O)cccc1Cl
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: C1CCNC1
Product: CCOC(=O)C1Oc2cccc(Cl)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 24.4 %

Procedure:
(E)-4-Oxo-but-2-enoic acid ethyl ester (4.60 mL, 38.32 mmol), 2-nitrobenzoic acid (1.08 g, 6.39 mmol), and pyrrolidine (0.53 mL, 6.39 mmol) were added simultaneously to a solution of commercially available 2-chloro-6-hydroxy-benzaldehyde (5.0 g, 31.93 mmol) in dimethysulfoxide (30 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel Flash column chromatography using ethyl acetate-hexanes (1:1.2) as eluents, yielding 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a solid (2.08 g, 49.5%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6]=[CH:5][CH2:4][CH:3]=1.Cl[C:9](=[CH2:12])[C:10]#N.[C:13]1([CH:20]=[CH:19][C:17]([OH:18])=[CH:16][CH:15]=1)[OH:14]>>[CH3:1][C:2]12[CH2:12][CH2:9][CH:5]([CH:6]=[CH:7]1)[C:4](=[O:14])[CH2:3]2.[CH3:1][C:19]12[CH2:10][CH2:9][CH:15]([CH:13]=[CH:20]1)[CH2:16][C:17]2=[O:18]
Reactant: Oc1ccc(O)cc1
Reactant: C=C(Cl)C#N
Reactant: CC1=CCC=CC1
Product: CC12C=CC(CC1)C(=O)C2
Product: CC12C=CC(CC1)CC2=O
Reaction time: 0.5 h

Procedure:
A mixture of 1-methyl-1,4-cyclohexadiene and 2-chloroacrylonitrile was heated for 14 hours at 110° C. in the presence of hydroquinone as polymerization inhibitor. The raw product was distilled at 60° to 65° C./0.13 millibars and the distillate was hydrolyzed in an aqueous solution of potassium hydroxide in dimethyl sulfoxide for 30 minutes at 120° C. The mixture was hereafter poured on ice. Extraction with penetane and separation by chromatography on a silica gel column resulted in a 5:1 mixture of 4-methyl-bicyclo[2.2.2]oct-5-en-2-one and 1-methyl-bicyclo[2.2.2]oct-5-en-2-one in a yield of 50 to 55%.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[N:13])C.C(O[CH:18](OCC)[CH2:19][NH2:20])C>CO>[ClH:1].[NH:20]1[CH:19]=[CH:18][N:14]=[C:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[N:13]
Reactant: CCOC(CN)OCC
Reactant: CCOC(=N)c1ccccc1C#N
Agent: Cl
Solvent: CO
Product: N#Cc1ccccc1-c1ncc[nH]1
Yield: 3.6 %

Procedure:
A solution of 2-cyano-benzimidic acid ethyl ester hydrochloride (43 g, 0.20 mol) and 2,2-diethoxy-ethylamine (30 ml, 0.21 mol) in methanol (430 ml) was aged at room temperature for 1 h. The reaction mixture was concentrated to remove methanol and conc. sulfuric acid (110 ml) was added. After heating on a steam bath for 1.5 h, the reaction mixture was diluted with water (700 ml) and extracted with chloroform. The aqueous phase was made strongly basic with sodium hydroxide and extracted with chloroform. Hydrochloric acid (12N) was added to give pH 3-4, tar was filtered and the filtrate was concentrated. The resultant brown solid was sublimed at 200-220° C. The purified solid was dissolved in hydrochloric acid solution (6N, 110 ml), byproducts filtered and the filtrate concentrated. The residue was diluted with ethanol (100-120 ml) containing hydrochloric acid (12N, 1 ml), boiled briefly and filtered. Further concentration and cooling of the filtrate gave 2-(1H-imidazol-2-yl)-benzonitrile hydrochloride (1.5 g). The filtrate was concentrated further and diluted with acetone. Filtration gave 2-(1H-imidazol-2-yl)-benzoic acid hydrochloride (7.3 g). Dilution of the filtrate with acetone and filtration of the resultant solid gave additional 2-(1H-imidazol-2-yl)-benzonitrile hydrochloride; mp 200-204° C.; IR 4.5μ.
Reaction SMILES: C(OCC1C=C(C2N=C3CCCN3C=2C2C=CN=CC=2)SC=1)(=O)C.[SH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH2:45][CH2:44][CH2:43][N:35]3[C:36]=2[C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:28][CH:27]=1.C(N(CC)CC)C.[CH:53]1[CH:58]=[CH:57][C:56]([O:59][C:60](Cl)=[S:61])=[CH:55][CH:54]=1>COCCOCCOC>[O:59]([C:60]([S:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:34]3[CH2:45][CH2:44][CH2:43][N:35]3[C:36]=2[C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:30][CH:31]=1)=[S:61])[C:56]1[CH:57]=[CH:58][CH:53]=[CH:54][CH:55]=1
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CC(=O)OCc1csc(-c2nc3n(c2-c2ccncc2)CCC3)c1
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: S=C(Oc1ccccc1)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice-bath cooled solution containing 1.0 q (3.4mmole) of 2 (4-mercaptophenyl) 3 (4-pyridyl) 6,7dihydro[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of diglyme is added 0.48 ml (3.5mmole) of phenyl chlorothionoformate. The reaction is allowed to warm to room temperature and heated at 40° to 120° C. for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[N+:6]([C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]([Cl:19])[C:10]=1[NH2:11])([O-:8])=[O:7].[N:20](OS(=O)(=O)O)=O>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[N+:6]([C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]([Cl:19])[C:10]=1[N+:11]#[N:20])([O-:8])=[O:7].[N+:6]([C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]([Cl:19])[C:10]=1[N+:11]#[N:20])([O-:8])=[O:7]
Reactant: O=NOS(=O)(=O)O
Reactant: O=S(=O)(O)O
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: N#[N+]c1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: O=S(=O)([O-])[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1000 Parts by weight of 100% sulfuric acid are placed into a stirring flask. 217.5 Parts by weight of 100% 2,4-dinitro-6-chloroaniline are then introduced in a way that the temperature of 40° C. is not exceeded. After the entire 2,4-dinitro-6-chloroaniline has been dissolved, 334 parts by weight of 40% nitrosyl-sulfuric acid are introduced, starting at a temperature of from 20° to 25° C., in such a manner that the temperature rises by itself to 35° to 38° C. Subsequently the mixture is continued to be stirred for 2 hours. A test is made to find out whether a sample is clearly soluble in ice water. After the diazotization has been completed, the mixture is cooled to +20° C., and the solution thus obtained of 2,4-dinitro-6-chlorobenzene-diazonium sulfate is added to an agitated mixture of 1500 parts by weight of water, 2000 parts by weight of ice, 224 parts by weight of 2-amino-4-acetamino-1-β-methoxy-ethoxy-benzene and 100 parts by weight of acetic acid within 30 minutes. During the addition process the temperature is maintained at 0° C. by adding about 3000 parts by weight of ice. Stirring is continued for 30 minutes, then the mixture is diluted with 6000 parts by weight of water and stirred for another hour. Finally the dyestuff formed is filtered off and washed with water until it is free from acid.
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C.C(Cl)(Cl)Cl>[CH:6]1[CH:5]=[CH:4][C:3]([N:2]([C:6]2[CH:5]=[CH:4][C:3]([NH2:2])=[CH:8][CH:7]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:8][CH:7]=1
Reactant: Nc1cccc(B(O)O)c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
(N,N′-Bis(m-(boronic acid)phenyl)-1,5-bis(phenyl)anthracene-2,3,6,7-tetracarboxyl diimide (47): A mixture of 1,5-bis(phenyl)anthracene-2,3,6,7-tetracarboxyl bisanhydride (0.10 g, 0.22 mmol), 3-aminophenyl boronic acid monohydrate (0.99 g, 0.64 mmol) in 5 ml of acetic acid was reacted and worked up according to the procedure for coupling yielding a yellow solid. Product was dissolved in and heated slightly in chloroform. The chloroform was removed by vacuum filtration and the final product, a yellow solid, was dried in a vacuum oven. 1H NMR (300 MHz, CDCl3): δ 7.31-7.63 (m, 9H), 8.52 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[C:5]2[S:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.[CH:40]1([NH:43][C:44](=[O:62])[C:45]2[CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[C:48]([CH3:60])=[C:47]([F:61])[CH:46]=2)[CH2:42][CH2:41]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C:14]([CH3:25])([CH3:24])[CH2:13][N:7]1[CH:6]=[C:5]([S:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28]2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:49]3[CH:50]=[C:45]([C:44](=[O:62])[NH:43][CH:40]4[CH2:41][CH2:42]4)[CH:46]=[C:47]([F:61])[C:48]=3[CH3:60])[CH:3]=2)[C:8]1=[O:12])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1cc(SC2CCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccc2c1=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(SC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 42.2 %

Procedure:
A solution of tert-butyl 4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}piperidine-1-carboxylate (Example 58c, 0.248 g) in DMF (4 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.124 g), Pd-118 (0.007 g) and potassium carbonate (0.107 g). The reaction was stirred at 80° C. for 6 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate (2×100 mL), and the combined organics were washed with water (3×100 mL) and brine (3×100 mL). The organics were dried (MgSO4), filtered, and evaporated under reduced pressure. The crude product was purified (SiO2 chromatography, eluting with 10-50% ethyl acetate/isohexane) to afford the subtitle compound (0.123 g).
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][NH:5][CH3:6].[CH3:7][CH:8]([CH3:14])[CH2:9][CH2:10][C:11](=[O:13])[CH3:12].[OH-].[Na+]>CCOCC.CO>[CH3:4][N:5]([CH2:1][CH:10]([CH2:9][CH:8]([CH3:14])[CH3:7])[C:11](=[O:13])[CH3:12])[CH3:6]
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)CCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(=O)C(CC(C)C)CN(C)C
Yield: 57.1 %

Procedure:
Paraformaldehyde (5.5 g, 183.33 mmol, 1.60 equiv) and dimethylamine hydrochloride (10 g, 122.70 mmol, 1.00 equiv) were added to a solution of 5-methylhexan-2-one (50 g, 437.83 mmol, 3.00 equiv) and methanol (30 mL). The resulting solution was heated at reflux for about 16 hours, and then the pH was adjusted to about 8 with sodium hydroxide (10%). Standard extractive workup with ether (3×100 mL) gave the title product as a yellow oil (12 g, yield=57%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:26]CC2C=CC(OC)=CC=2OC)=[N:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[F:25])=[O:16])=[CH:10][CH:9]=1)#[N:2].FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:26][C:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[F:25])=[O:16])=[CH:10][CH:9]=2)[S:6][N:5]=1
Reactant: COc1ccc(CNc2nsc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2C#N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(N)c3C#N)cc2)c1
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A suspension of 1-(4-{4-cyano-3-[(2,4-dimethoxybenzyl)amino]isothiazol-5-yl}phenyl)-3-(2-fluoro-5-methylphenyl)urea (593 mg, 1.15 mmol) in 50 mL of CH2Cl2 was treated with 1.5 mL of trifluoroacetic acid. Solid was dissolved and the reaction turned to yellow and then red in color. TLC indicated the completion of the reaction in <30 min. Saturated Na2CO3 solution was added and the mixture was stirred for 30 min. Layers were separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine and dried with MgSO4, filtered, and concentrated. The crude product was redissolved in 100 mL of EtOAc. Insoluble impurity was filtered through celite and washed with EtOAc. Filtrate was concentrated in vacuo to afford the title compound as a cream solid (398 mg, 94%).
Reaction SMILES: O.[CH:2]([O-:4])=[O:3].[NH4+].Cl[C:7]1[S:8][C:9](Cl)=[C:10]2[C:14](=C=O)[N:13](OC(C)(C)C)[CH2:12][C:11]=12>CO.[Pd]>[CH3:9][C:10]([CH3:14])([O:3][C:2]([N:13]1[CH2:12][C:11]2=[CH:7][S:8][CH:9]=[C:10]2[CH2:14]1)=[O:4])[CH3:11]
Reactant: O=C[O-]
Reactant: CC(C)(C)ON1Cc2c(Cl)sc(Cl)c2C1=C=O
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cscc2C1
Yield: 134.3 %

Procedure:
17.6 g of 10% palladium-on-charcoal containing 50% of water and then 41.6 g (600 mmol) of ammonium formate are added to a solution of 8.82 g (30 mmol) of 1,3-dichloro-5(1,1-dimethylethoxy)-carbonyl-5,6-dihydro-4H -thieno[3,4-c]pyrrole in 75 ml of methanol. The mixture is heated at reflux for 24 hours and it is then cooled, filtered through a Celite column, rinsed with twice 50 ml of dichloromethane and evaporated to dryness. The residue is taken up in 100 ml of dichloromethane, filtered and evaporated to dryness. There are obtained 4.54 g of an oily product which crystallizes slowly. Yield 68%. Melting point: 36°-38° C.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1B(O)O.FC1C=C(F)C=CC=1C1C=CC2C(=CC=C(OC)C=2)C=1C(C1C=CC(OCCN2CCCCC2)=CC=1)=O>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[CH:42]=[CH:43][C:44]([F:46])=[CH:45][C:40]=3[F:39])=[O:16])=[CH:37][CH:38]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Yield: 85.3 %

Procedure:
Couple trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (1.4 g, 2.5 mmol) and 2,4-difluorophenyl boronic acid (1.2 g, 7.6 mmol) by the procedure used to prepare [2-(2,4-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give yields 1.1 g (85%) of the title compound: mass spectrum (ion spray) m/z=516.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[NH:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:22]([O:26][C:27]([N:29]1[CH:38]([C:39](=[O:53])[NH:40][CH:41]([C:50](O)=[O:51])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH:38]([C:39](=[O:53])[NH:40][CH:41]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:50]([N:10]2[CH2:11][CH2:12][N:7]([CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:5][NH:4][C:3]([O:2][CH3:1])=[O:21])[CH2:8][CH2:9]2)=[O:51])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)NCC(c1ccc(F)cc1F)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NC(Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCC(c1ccc(F)cc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To [2-(2,4-Difluoro-phenyl)-2-piperazin-1-yl-ethyl]-carbamic acid methyl ester (516) (0.14 g, 0.47 mmol), 3-[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.22 g, 0.47 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.178 g, 0.47 mmol) was added MeCl2 (1.0 mL) and DMF (0.2 mL) followed by DIPEA (0.82 mL, 4.7 mmol). The reaction was allowed to stir at room temperature for 4 h. The reaction mixture was then concentrated to dryness. The resulting residue was taken up in EtOAc (30 mL) and washed with sat. NaHCO3 (30 mL) and brine (30 mL). The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with a gradient of 100% EtOAc to 5% TEA/5% MeOH in EtOAc) yielding 0.34 g (98%) pure product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].[NH:39]([C:43]1[S:44][CH:45]=[C:46]([CH2:48][S:49][CH2:50][CH2:51][NH2:52])[N:47]=1)[C:40]([NH2:42])=[NH:41]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]([NH:52][CH2:51][CH2:50][S:49][CH2:48][C:46]2[N:47]=[C:43]([NH:39][C:40]([NH2:42])=[NH:41])[S:44][CH:45]=2)=[O:28])[CH3:20])=[CH:4][CH:3]=1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCCCCCN)CCC(c1ccc(F)cc1)c1ccccn1
Solvent: ClCCl
Product: CN(CCCCCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.9 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.65 g (2.8 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: methylene chloride) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=615 ([M+H]+ 2), 214 (100); IR (KBr): 1632 cm-1 (C=O).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>CN(C)C=O.C(OCC)(=O)C.O>[I:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[N:8]=[CH:7]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Ic1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.6 %

Procedure:
To a slurry of sodium hydride (0.67 g, 17 mmol) in N,N-dimethylformamide (43 mL) cooled to 0° C. was added 5-iodo-1H-indazole (3.1 g, 13 mmol). After stirring for 15 min, triisopropylsilyl chloride (3.4 mL, 17 mmol) was added dropwise and the solution was allowed to warm to room temperature. The solution was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was extracted (2×100 mL ethyl acetate) and the combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 20:1 hexanes/ethyl acetate) gave 1.8 g (68%) of 5-iodo-1-[tris(1-methylethyl)silyl]-1H-indazole as a yellow solid. 1H NMR (400 MHz, CDCl3): 8.14 (d, 1H), 8.11 (d, 1H), 7.55 (dd, 1H), 7.35 (d, 1H), 1.77 (m, 3H), 1.10 (m, 18H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][S:32][CH2:31][CH2:30]4)=[C:25]([CH3:35])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[CH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1)[O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:36])=[O:5])[CH2:14][CH2:13]2)=[CH:16][CH:17]=1
Reactant: Cc1cc(OCc2ccc(C3CCN(CCC(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCSCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(C3CCN(CCC(=O)O)CC3)cc2)ccc1C1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude 3-(4-{4-[3-Methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidin-1-yl)-propionic acid tert-butyl ester in dry DCM (7 mL) is added triethyl silane (5 eq., 4.442 mmol, 517 mg, 0.71 mL) followed by TFA (7 mL). The resulting mixture is stirred at room temperature for 1 hour. After concentration, the crude product is purified by preparative RP LC-MS to give 3-(4-{4-[3-methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidin-1-yl)-propionic acid as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.44-7.38 (m, 2H), 7.30-7.21 (m, 2H), 7.13-7.05 (m, 1H), 6.83-6.72 (m, 2H), 5.02 (s, 2H), 3.61-3.52 (m, 2H), 3.15-3.05 (m, 2H), 2.89-2.75 (m, 5H), 2.72-2.60 (m, 3H), 2.33-2.20 (m, 3H), 2.06-1.88 (m, 6H), 1.77-1.61 (m, 1H); MS (ES+): (454.2, M+1)+.