Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:18][C:19]([CH3:21])=[CH2:20])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:20][C:19](=[O:18])[CH3:21])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 68.3 %

Procedure:
To a stirred solution of 4-bromo-4'-chlorobiphenyl (16 g; F. R. Shaw and E. E. Turner. J. Chem. Soc., 285 (1932) ), isopropenyl acetate (9 g) and dichlorobis(tri-o-tolylphosphine)palladium (0.47 g) in dry toluene (30 ml), under nitrogen, was added tributyltin methoxide (25.9 ml; Aldrich). The mixture was stirred and heated at 100° for 5 hr, cooled and the solvent evaporated in vacuo. The residue was chromatographed on silica gel, eluting with cyclohexane then ether. The resultant solid was recrystallised from cyclohexane to afford the title compound (10 g), m.p. 79°-81°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C.C1COCC1.C(OCC)C>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccccc1CCl
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A suspension of Mg (3.50 g, 144 mmol) in diethyl ether (75 mL) was treated with 2-fluorobenzyl chloride (19.0 g, 131 mmol), stirred until all the Mg dissolved, treated with N-benzyl 4-piperidone (27.2 g, 144 mmol) in RATIO THF/diethyl ether (40 mL), and stirred at room temperature until the reaction was complete by TLC analysis. The mixture was partitioned between ethyl acetate and saturated NH4Cl and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4), filtered, and concentrated to give a residue which was used without further purification. MS (ESI) m/e 300 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CCCCCC>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:43])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (66.2 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.5 ml) at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3) to provide the titled compound (49.5 mg, 55%) as white powder.
Reaction SMILES: BrCC(Br)=O.[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[C:8]=1[NH2:9].[Br:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Br:19][CH2:20][CH2:21][C:22]([NH:9][C:8]1[C:10]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=[CH:13][C:7]=1[CH3:6])=[O:23]
Reactant: CCCC(=O)c1cccc(C)c1N
Reactant: O=C(Cl)CCBr
Agent: O=C(Br)CBr
Product: CCCC(=O)c1cccc(C)c1NC(=O)CCBr

Procedure:
In the same manner as in Example 1 but replacing 2-acetyl-6-methylaniline and bromoacetyl bromide by 2-methyl-6-n-butanoylaniline and 3-bromopropionyl chloride, there was obtained 3-bromo-2'-methyl-6'-n-butanoylpropionanilide. [B] Amination
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:16]=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C1(C=CC(O)=CC=1)O.C1C(=O)N([Br:33])C(=O)C1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([Br:33])=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2Cc3cc(C)sc3C2C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC2Cc3c(sc(C)c3Br)C2C1
Temperature: 40 °C

Procedure:
The product of Example 15, step c) (69.1 mg, 0.30 mmol) was placed in a vial and diluted with CHCl3 (740 μl) and AcOH (740 μl). Next, hydroquinone (˜5 mg) was added followed by NBS (51.4 mg, 0.31 mmol) and the contents were heated to 40° C. for 6 hours. The crude reaction mixture was carefully poured into saturated NaHCO3 (10 ml) and extracted with EtOAc (3×5 ml). The organic layer was dried (MgSO4) and purified by preparative TLC using hexanes/EtOAc 50:50 providing the subtitled product. MS calculated for C13H16BrNO2S+H 330, observed 330, 332.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([Br:16])=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[OH-].[K+].[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.O>[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][C:13]([Br:16])=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:33][CH:34]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccc(Br)s3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product of Example 241b (1.50 g, 4.34 mmol) was dissolved in DMF to which KOH (469 mg, 8.69 mmol), and (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester (909 mg, 4.34 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water that was then extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound to provide the title compound (2.11 g, 90%).
Reaction SMILES: CS([Cl:5])(=O)=O.[CH:6]1([NH:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH:6]1([NH:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][Cl:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCCCN(CCO)Cc1ccccc1)NC1CCCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCN(CCCl)Cc1ccccc1)NC1CCCCCC1
Temperature: 20 °C
Yield: 100.5 %

Procedure:
Methanesulfonyl chloride (0.78 g, 0.52 ml, 6.6 mmole) is added dropwise with stirring to a cooled solution of N-cycloheptyl-5-[benzyl(2-hydroxyethyl)amino]pentanamide (2.14 g, 6 mmole) in dichloromethane (20 ml) in the presence of triethylamine (0.69 g, 0.94 ml, 6.6 mmole). Agitation is maintained for 18 hours at 20° C. The reaction mixture is filtered with iced water (25 ml) then dried over magnesium sulfate. Filtration and evaporation of the solvent under reduced pressure give 2.2 g (98%) of the desired compound in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:18]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:18][CH:17]([CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:26])[C:16]([O:15][CH3:14])=[O:27])=[O:13])=[CH:5]2
Reactant: COC(=O)[C@@H](N)C(C)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: COC(=O)C(NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(C)c1ccccc1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and DL-β-methylphenylalanine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+:11]([O-])(O)=O>C(O)(=O)C.C(O)C.[Pd]>[NH2:11][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(O)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cc(N)c(O)cc1F

Procedure:
This was prepared from 2-fluoro-4-hydroxy-benzonitrile by nitration (concentrated nitric acid in acetic acid at 40° C.) followed by hydrogenation in ethanol over 10% palladium/carbon.
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([N:18]=[CH:19]N(C)C)=[S:17])[CH:10]=1)(=[O:8])=[O:7])C.[CH2:23](Br)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].Cl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:24]([C:23]1[S:17][C:16]([NH:15][C:11]2[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=2)=[N:18][CH:19]=1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C=NC(=S)Nc1cccc(S(=O)(=O)N=CN(C)C)c1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccc(Nc2ncc(C(=O)c3ccccc3)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
A mixture of 44 mg (0.13 mmol) N-Dimethylaminomethylene-3-(3-dimethylaminomethylene-thioureido)-benzenesulfonamide and 26 mg (0.13 mmol) phenacyl bromide in 0.8 ml DMF was stirred for 16 h at room temperature. 0.12 ml HCl (37%) was added and the mixture was stirred for 69 h at 100° C. After addition of 0.12 ml N,N-Diisopropylethylamine the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 6 mg (13%) of the title compound.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]1([CH3:36])[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:21]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O.ClCCl.O.[Ru](Cl)(Cl)Cl>[O:2]=[C:24]1[N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:21][CH:20]1[O:19][CH2:18][CH2:17][O:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:36])=[CH:8][CH:9]=1)(=[O:14])=[O:15]
Reactant: COC(=O)C1CC(OCCOS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CC(OCCOS(=O)(=O)c2ccc(C)cc2)C(=O)N1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 24 %

Procedure:
A solution of 1.07 g (5.0 mmol) of sodium periodate and 0.338 g (0.15 mmol) of ruthenium(III) chloride hydrate in 12.5 ml of water was added to 0.44 g (1 mmol) of 1-tert-butyl 2-methyl 4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate in 20 ml of dichloromethane. The mixture was left at room temperature for three days with vigorous stirring. Subsequently, the phases were separated, the aqueous phase was extracted twice with ethyl acetate (20 ml) and the combined organic phases were stirred with 5 ml of isopropanol for 30 min. The mixture was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate). 0.11 g (24%) of 1-tert-butyl 2-methyl 5-oxo-4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate (23) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:11].[Cl:12][C:13]1=[C:14]([Cl:20])[C:15]([O:17][C:18]1=[O:19])=[O:16]>C(Cl)CCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:15](=[O:16])[C:14]([Cl:20])=[C:13]([Cl:12])[C:18]([OH:19])=[O:17])=[C:3]1[CH3:11]
Reactant: Cc1cc2ccccc2n1C
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: ClCCCl
Product: Cc1c(C(=O)C(Cl)=C(Cl)C(=O)O)c2ccccc2n1C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A mixture of 10.0 g (0.07 mole) of 1,2-dimethylindole, 12.0 g (0.07 mole) of dichloromaleic anhydride and 200 ml of ethylene dichloride was stirred at ambient temperature for approximately eighteen hours. The solid present in the reaction mixture was collected by filtration. After drying at 60° C. in vacuo there was obtained 20.0 g of 4-(1,2-dimethyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid (Formula VIII: R=R1 =CH3 ; Y=H) as a pale blue solid which melted over the range 150° to 153° C. Infrared spectral analysis showed a maximum at 1712 (C=0; s) cm-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: NN
Reactant: Clc1ccc(Br)cn1
Solvent: O
Product: NNc1ccc(Br)cn1
Temperature: 70 °C
Yield: 83 %

Procedure:
2-Chloro-5-bromopyridine (64 g, 333 mmol) was suspended in hydrazine monohydrate (250 mL) and the mixture was heated at 70° C. for 72 hours. The reaction mixture was then diluted with water (750 mL) and the resulting precipitate was filtered off and azeotroped, firstly with toluene (×2) then dichloromethane (×2), to afford the title compound as a pale brown solid in 83% yield, 52 g.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].CO.[CH2:17]1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzoic acid (2.6 g, 10 mmol), MeOH (320 mg, 10 mmol) and DMAP (122 mg, 1 mmol) in methylene chloride (40 mL) was added DCC (2.06 g, 10 mmol) and the resulting mixture was stirred at ambient temperature for 2 h. The resulting precipitate was filtered and the filtrate evaporated under reduced pressure. The resulting oil was filtered through a plug of silica gel using methylene chloride as eluent. The solvent was removed under reduced pressure to give 4-bromomethyl-3-nitrobenzoic acid methyl ester as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1.BrC1C=CC=CN=1>[Pd]>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1
Reactant: COCc1csc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: Brc1ccccn1
Product: COCc1csc(NC(=O)c2nc(C)ccc2Nc2cncnc2)n1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 4-Methoxymethyl-thiazol-2-ylamine (CAS: [640768-40-7]; WO 2004081001) instead of 2-chloro-4-aminopyridine to yield [2-(4-Methoxymethyl-thiazol-2-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester as an off-white gum, MS (ISP): m/e=379.4 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methoxymethyl-thiazol-2-yl)-amide as an off-white solid, MS (ISP): m/e=279.3 (M+H+). Palladium catalysed arylation in accordance with the general method of example 20, using 5-Bromopyrimidine instead of 3 bromopyridine yielded the final compound as a light yellow solid, MS (ISP): m/e=357.1 (M+H+).
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=O)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1>>[CH:5]1([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([NH:52][CH2:51][C:48]3[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=3)=[O:17])[C:8]2=[O:22])[CH2:23][CH2:24]1
Reactant: NCc1ccncc1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1ccncc1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 60 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with pyridin-4-ylmethanamine, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-4-ylmethyl)isonicotinamide was obtained as a colorless solid in 60% yield: mp 160-162° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.7-8.52 (m, 3H), 8.37 (d, J=5.1 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H), 7.31-7.15 (m, 3H), 4.60 (d, J=4.5 Hz, 2H), 4.06 (t, J=8.1 Hz, 2H), 3.59 (t, J=8.1 Hz, 2H), 3.13 (d, J=6.9 Hz, 2H), 0.99-0.91 (m, 1H), 0.60-0.49 (m, 2H), 0.29-0.15 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 156.9, 153.2, 149.8, 148.5, 147.3, 142.2, 122.5, 115.8, 108.8, 48.6, 42.8, 41.6, 41.5, 9.0, 3.4; MS (ES+) m/z 352.3 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][C:23]([C:25]([NH:27][C@@H:28]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:29](O)=[O:30])=[O:26])=[CH:24][C:19]2=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][C@H:28]([NH:27][C:25]([C:23]2[NH:22][C:20]3=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=[C:19]3[CH:24]=2)=[O:26])[C:29](=[O:30])[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:38][CH:37]=1
Reactant: C1CCNC1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2ccc(Cl)nc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCCC1)c1cc2ccc(Cl)nc2[nH]1

Procedure:
To pyrrolidine (11.5 mg, 0.14 mmol) was added a solution of DIPEA (60 μL, 0.35 mmol) in DMF (500 μL) followed by 2-(S)-[(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl) propionic acid (EXAMPLE 272, 50 mg, 0.14 mmol) in DMF (500 μL) and HOBt (23 mg, 0.15 mmol) in DMF (500 μL) and the mixture stirred. After 5 min EDCI (34.5 mg, 0.18 mmol) in DMF (500 μL) was added and the reaction stirred for 16 hr. Solvent was removed in vacuo then crude material purified by mass-directed purification to give the title compound. m/z (ES+)=414.93 [m+H]+; RT=3.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1)#[N:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:35]([C:34]3[CH:33]=[N:32][C:31]([C:29]#[N:30])=[CH:39][CH:38]=3)=[O:36])[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: N#Cc1ccc(C(=O)O)cn1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(C#N)nc3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(6-cyano-pyridine-3-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 6-cyanonicotinic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown oil. MS m/e: 543.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[OH-].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:8]=2)[CH:3]=1
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc2cc(Br)ccc2c1

Procedure:
22.29 g (0.1 mol) of 2-bromo-6-naphthol, 11.22 g (0.2 mol) of potassium hydroxide, and 32.36 g (0.13 mol) of 1-bromododecane were dissolved in ethanol (300 ml), and the solution was refluxed for 8 hr. Thereafter, water was added thereto, the mixture was cooled, and the resultant precipitate was collected by filtration and washed with a sodium hydroxide solution and then with water. The crude product thus obtained was recrystallized from ethyl acetate to give 2-bromo-6-dodecyloxynaphthalene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C1COCC1.CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 135 °C
Reaction time: 0.23 h
Yield: 78 %

Procedure:
To 3-nitro-N-phenylbenzenesulfonamide (255.5 mg, 0.919 mmol) in 4 mL of THF is added SnCl2 dihydrate (1.015 g, 4.486 mmol). The resulting mixture is heated in a microwave reactor at a power of 75 Watts and 135° C. for 1 min then at 15 Watts and 135° C. for 14 min. The reaction is cooled to room temperature, diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3 (10 mL) and allowed to stir for about 12 hours. The reaction mixture is then extracted with EtOAc (75 mL). The organic layer is washed with H2O (75 mL), saturated aqueous NaCl (2×75 mL), dried (MgSO4) and concentrated in vacuo to yield a yellow residue. This residue is purified over silica (0-4% MeOH in CH2Cl2) to afford 178 mg (78% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 5.57 (s, 2H), 6.69 (d, J=8.1 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.95 (s, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.07 (d, J=8.1 Hz, 2H), 7.12 (t, J=8.1 Hz, 1H), 7.21 (t, J=8.1 Hz, 2H), 10.12 (s, 1H). MS (ESI, pos. ion) m/z: 249 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)=[O:5])C.[OH-].[K+].O>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)([OH:5])=[O:3]
Reactant: CCCCCCCCCCOc1ccc(Oc2cccc(C(=O)OCC)c2)cc1CCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCOc1ccc(Oc2cccc(C(=O)O)c2)cc1CCC(=O)O
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A solution of 510 mg of 5-(3-ethoxycarbonylphenoxy)-2-(decyloxy)benzenepropanoic acid in 20 ml of ethanol was treated with an excess of potassium hydroxide in a small amount of water. After stirring for 18 hours, the solution was concentrated in vacuo. Diethyl ether and water added, the layers were separated, and the aqueous layer was acidified with 1N hydrochloric acid. The aqueous layer was extracted with diethyl ether, and this extract was dried over sodium sulfate and concentrated in vacuo. Two crystallizations from ethyl acetate/hexane provided 200 mg of the desired title product, m.p. 102°-104° C.