Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[N:6]#[O+].[F:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[NH2:11]>C(#N)C.C(OCC)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[N+:11]#[N:6]
Reactant: N#[O+]
Reactant: Nc1cc(F)ccc1F
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: N#[N+]c1cc(F)ccc1F
Reaction time: 1 h

Procedure:
Nitrosonium tetrafluoroborate (905 mg, 7.75 mmol, 1.00 equiv) was added to a solution of 2,5-difluoroaniline (0.780 mL, 7.75 mmol, 1 equiv) in acetonitrile (50 mL) at 0° C. The resulting mixture was stirred for 1 hour, then diluted with ethyl ether (150 mL). The precipitate was filtered and air-dried to give 2,5-difluorobenzenediazonium tetrafluoroborate (1-1) as a tan solid. 1H NMR (300 MHz, CD3OD) δ 8.54 (m, 1H), 8.24 (m, 1H), 7.95 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[CH:22]2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH:40]([NH2:43])[CH2:41][CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:33][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[C:26]([C:30](=[O:31])[NH:43][CH:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:41][CH3:42])[CH:25]=2)[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:9]3[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:15][CH:16]=2)[CH:22]=1
Reactant: Cc1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CCC(N)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(c1)c(C)cn2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-3-methyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CN1CCNCC1
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and 1-methylpiperazine following the procedure outlined in Example 15 (modifications: 25° C., overnight). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 10.09 (s, 1H), 8.82 (s, 1H), 8.59 (s, 2H), 7.88 (d, 1H), 7.06 (d, 1H), 4.99 (s, 1H), 3.98 (t, 2H), 3.91 (s, 3H), 3.75-2.90 (br, 10H), 2.77 (s, 3H), 2.22 (s, 6H), 1.77 (m, 2H), 1.69 (m, 2H), 1.44 (m, 2H), 1.36 (m, 2H); MS (ESI): 494.4.
Reaction SMILES: N1C=CC=CC=1C[C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[C:25](O)(=O)[CH3:26]>[Pd]>[NH:10]1[CH2:9][CH2:8][CH2:24][CH2:23][CH:25]1[CH2:26][C:17]1[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=1[C:11]([NH:10][C:9]1[CH:8]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:20]
Reactant: COc1ccc(C(=O)Nc2ccccc2Cc2ccccn2)cc1
Reactant: CC(=O)O
Agent: [Pd]
Product: COc1ccc(C(=O)Nc2ccccc2)c(CC2CCCCN2)c1

Procedure:
Reduction of 2'-(2-pyridylmethyl)-p-anisanilide (4.65 g., 0.0146 mole) according to the procedure of Walker, J. Org. Chem., 27, 2966 (1962), in 150 ml. of acetic acid with 2.35 g. of 10% palladium on carbon catalyst affords 2'-(2-piperidylmethyl-p-anisanilide, m.p. 108° -109° C. (corr.), from benzene-hexane.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=[C:14]2[C:13]1=[O:23])[CH3:2].[H][H]>C(OCC)(=O)C.[Ni]>[CH2:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=[C:14]2[C:13]1=[O:23])[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Yield: 53.3 %

Procedure:
The solution of 1.65 g of N-(2-ethyl-4-nitrophenyl)-4-chlorophthalimide in 80 ml of ethyl acetate is hydrogenated over 5 g of Raney Nickel at 2.5 atm. of hydrogen pressure for 5 hours. After filtration the residue of 1.5 g is crystallized from ethyl acetate-hexane to give 800 mg of the N-(2-ethyl-4-aminophenyl)-4-chlorophthalimide melting at 118°-120°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.Br[CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[O:9][CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Br)CC(C)C
Reactant: OC(c1ccc(Br)cc1)c1nccs1
Product: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1nccs1

Procedure:
Using the same protocol as described in example 23, step 2, (4-bromophenyl)(1,3-thiazol-2-yl)methanol from step 1 (983 mg, 3.64 mmol) was added to methyl 2-bromo-4-methylpentanoate (624 μL, 3.82 mmol). The crude residue was chromatographed on silica gel using 25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(I)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1ccc(I)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 2-fluoro-4-iodobenzoic acid (5.00 g, 18.0 mmol), oxalyl chloride (2.0 mL, 22.0 mmol), ammonia gas, DCM (100 mL) and THF (100 mL) to afford 2.00 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.40 (t, J=7.8 Hz, 1H), 7.63-7.76 (m, 1H); MS (m/z): 266.19 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:4]1[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=3[CH:16]=[C:2]([Cl:1])[CH:3]=1)=[O:19])[CH2:24]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cc(Cl)cc2nc(-c3ccccc3)oc12
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cc(Cl)cc2nc(-c3ccccc3)oc12
Yield: 56 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-phenylbenzoxazole-7-carboxamide was prepared from 5-chloro-2-phenyl-benzoxazole-7-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 56% yield as a white solid: mp 283-285° C.; 1H NMR (300 MHz, CH3OD) δ 8.22 (dd, J=8.1, 1.5 Hz, 2H), 7.86 (d, J=2.1 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.64-7.56 (m, 3H), 4.27-4.24 (m, 1H), 3.50-3.42 (m, 1H), 3.12-2.86 (m, 5H), 2.17 (q, J=3.0 Hz, 1H), 2.11-2.06 (m, 1H), 1.85-1.73 (m, 2H), 1.74-1.67 (m, 1H); MS (ESI) m/z 382[M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([CH3:17])[C:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:18][OH:19])[CH3:2].[Mn]([O-])(=O)(=O)=[O:21].[K+]>>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([CH3:17])[C:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[C:4]1[C:18]([OH:21])=[O:19])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCC(=O)c1cc2nc(CO)n(CC)c2cc1C
Agent: [K+]
Product: CCCC(=O)c1cc2nc(C(=O)O)n(CC)c2cc1C

Procedure:
In a manner analogous to that described in Example 12, 5.2 g of 1-ethyl-5-butyryl-6-methyl-benzimidazole-2-methanol can be oxidised with 4.5 g of potassium permanganate to give 1-ethyl-5-butyryl-6-methyl-benzimidazole-2-carboxylic acid with a melting point >80° (decomposition).
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].CCCCCC.[CH:12]1[C:24]2[CH2:23][C:22]3[C:17](=CC=CC=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C(OCC)C>[C:1]1([Li:5])[C:22]2[CH2:23][C:24]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
With stirring, 113 ml of a 1.6 M solution of n-butyllithium in hexane (0.18 mol) were added to a solution of 25 g (0.15 mol) of fluorene in 220 ml of diethyl ether. To bring the reaction to completion, the mixture was boiled under reflux for 6 h and then stirred at room temperature overnight. The solvent was subsequently removed under reduced pressure and the resulting yellow powder was washed repeatedly with petroleum ether and dried under reduced pressure. This gave fluorenyllithium (compound II) in almost quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2ccc(F)cc2)c1
Yield: 82.6 %

Procedure:
Methyl 5-(4-fluorophenylthio)pyrrole-3-carboxylate (1.5 g.) was combined with 10 ml. of methanol and 10 ml. of 1N sodium hydroxide and refluxed for 2 hours. The methanol was allowed to evaporate, the aqueous residue was diluted with approximately one volume of water and extracted twice with ether. The aqueous phase was cooled in an ice-water bath and acidified to pH 2.0 with conc. hydrochloric acid. The gummy solid which precipitated was extracted into ethyl acetate. The three combined ethyl acetate extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Trituration with hexane gave crystalline 5-(4-fluorophenylthio)pyrrole-3-carboxylic acid (1.17 g., m.p. 116-118, m/e 237), recovered by filtration.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(Cc2ccccc2)c2ccccc12
Yield: 64 %

Procedure:
2-Chloro-1-benzyl-1H-indole-3-carboxaldehyde (1.0 g, 5.5 mmol) is reacted with piperazine as described in Example 2 to yield the title compound (64%), mp 163-165° C., as a pale yellow solid. MS 320 (M+H).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(O)C>[CH:1](=[N:12][CH2:11][CH2:10][N:13]=[CH:1][C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NCCN
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: Oc1ccccc1C=NCCN=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of salicylaldehyde (12.21 g/10.62 mL) in 70° C. ethanol (100 mL) was added ethylenediamine (3.01 g/3.33 mL). A yellow crystalline material immediately formed, and the reaction mixture was allowed to cool to room temperature with stirring. The solution was filtered, and the crystals were washed with cold ethanol. The ethanol layers were combined and reduced to approximately 20 mL and allowed to stand at 0° C. overnight. The resulting crystals were collected by vacuum filtration and washed with water. The collected solids were dried in vacuo to obtain 13.15 g (98%) N,N′-bis(salicylidene)ethylenediamine as yellow platelets with a melting point of 126° C. (literature value (24) 127-128° C.). 1H NMR (DMSO-d6) δ 8.57 (s 2H, HC=N), 7.42 (d, 2H aromatic, J=7.3 Hz), 7.31 (t, 2H, aromatic, J=9.0 Hz), 6.88 (t, 4H, aromatic, J=8.3, 16.1 Hz), 3.89 (s, 4H, CH2). 13C NMR (DMSO-d6) δ 166.94 (2C, CO−), 160.57 (2C, HC+N), 132.38 (2C, aromatic), 131.69 (4C, aromatic), 118.59 (2C, aromatic), 116.51 (2C, aromatic), 58.88 (2C, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:41]1([NH:47][C:48]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C=Nc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccccc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and phenylisocyanate (30 μl) instead of ethylisocyanate, in the same manner as Example 1-D-03, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid phenylamide was obtained, and then the PMB groups were removed according to Deprotection method 1′, to obtain the desired compound (D-28) as a yellow solid (4.2 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([OH:11])[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([O:22][CH2:23][CH2:24][Cl:25])[C:3]=1[C:26](=[O:28])[CH3:27].O.O.Cl[Sn]Cl.[CH3:34][CH2:35]O>>[C:26]([C:3]1[C:4]([O:22][CH2:23][CH2:24][Cl:25])=[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[O:11][C:34]([CH3:35])=[N:8][C:7]=2[C:2]=1[Cl:1])(=[O:28])[CH3:27]
Reactant: CC(=O)c1c(Cl)c([N+](=O)[O-])c(O)c(OCCCc2ccccc2)c1OCCCl
Reactant: CCO
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(=O)c1c(OCCCl)c(OCCCc2ccccc2)c2oc(C)nc2c1Cl
Temperature: 50 °C
Yield: 64 %

Procedure:
To a stirred solution 37h) (46 mg, 0.11 mmol) in dry EtOH (5 mL) under nitrogen was added SnCl2.2H2O (241 mg, 1.07 mmol). The solution was heated to reflux for 4 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc (5 mL) and treated with sodium potassium tartrate (1M, 5 mL). The mixture was warmed to 50° C. heated at this temperature until the layers visibly separated. The organic layer was separated and the aqueous further extracted with EtOAc (2×5 mL). The organics were pooled, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was taken up in dry DMF (3 mL) and to this solution triethyl orthoacetate (3 mL, excess) was added. The solution was stirred at reflux for 1 h. The solution was concentrated in vacuo and the residue was taken in CH2Cl2 (5 mL) and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate/petroleum spirit 3:18) to give the title compound (30 mg, 64%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.21 (m, 5H), 4.45-4.40 (t, J=6.6 Hz, 2H), 4.29-4.25 (m, 2H), 3.75-3.72 (t, J=5.7 Hz, 2H), 2.89-2.84 (t, J=7.2 Hz, 2H), 2.65 (s, 3H), 2.59 (s, 3H), 2.19-2.09 (m, 2H), ESIMS m/z [M+H]+ 422.2.
Reaction SMILES: [CH:1]([CH:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5])=O.Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][NH:21][CH3:22])[CH3:17]>C1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:23])[CH2:20][N:21]([CH3:22])[CH:1]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5])[CH3:17]
Reactant: Cc1cc(C)c(C(C#N)C=O)c(C)c1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)CN(C)C=C(C#N)c1c(C)cc(C)cc1C

Procedure:
A mixture of a-formyl-2,4,6 trimethylphenylacetonitrile (4.5 g, 24 mmol) and sarcosine ethyl ester hydrochloride (3.7 g, 24 mmol) in 100 mL of benzene was refluxed in a Dean-Stark apparatus for 16 h. The solvent was removed in vacuo to afford N-Methyl-N-[2-(2,4,6-trimethylphenyl)-2-cyanovinyl]-glycine ethyl ester as a pale yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:32])[N:16]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:17]2[CH2:22][C:23](OCC)=[O:24]>O>[CH2:28]([N:16]1[C:15](=[O:32])[C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[CH3:12])[CH:17]1[CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[CH:29]([CH3:31])[CH3:30]
Reactant: CCOC(=O)CC1c2cccc(C)c2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1cccc2c1C(=O)N(CC(C)C)C2CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 55.8 %

Procedure:
N-[2-(2-Isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 1, starting with 0.68 g of potassium tert-butoxide, 0.58 g of guanidinium chloride and 0.36 g of ethyl (4-methyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 20 cm3 of water. The aqueous phase is extracted with 3 times 100 cm3 of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure (0.5 kPa) at a temperature in the region of 40° C. The residue is taken up in dichloromethane and then concentrated again under the same conditions. The residue is taken up in water, triturated and filtered, and then taken up in dichloromethane, triturated and filtered. The solid is then dried in a desiccator. 0.21 g of N-[2-(2-Isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a white powder melting at 270-272° C. (decomposition). 1H NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.76 (d, J=7 Hz: 3H); 0.91 (d, J=7 Hz: 3H); 2.03 (mt: 1H); 2.42 (dd, J=15.5 and 6.5 Hz: 1H); 2.60 (dd, J=15.5 and 6.5 Hz: 1H); 2.62 (s: 3H); 3.00 (dd, J=14 and 5.5 Hz: 1H); 3.56 (dd, J=14 and 10 Hz: 1H); 4.98 (t, J=6.5 Hz: 1H); from 6.40 to 7.10 (broad multiplet: 2H); 7.21 (broad d, J=7.5 Hz: 1H); 7.36 (broad d, J=7.5 Hz: 1H); 7.42 (t, J=7.5 Hz: 1H); from 7.50 to 8.30 (broad multiplet: 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1)[NH2:6].CCN([CH:34]([CH3:36])[CH3:35])C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=1)[NH:6][C:15]([C:14]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:36]=1[CH2:34][CH3:35])=[O:26]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)C(=O)OC
Reaction time: 72 h
Yield: 122.8 %

Procedure:
A mixture of the above prepared acid chloride, 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-phenylalanine methyl ester hydrochloride (100 mg, 0.25 mmol) in dichloromethane (5 mL) was treated with DIPEA (0.17 mL, 1.0 mmol) and the resulting light brown solution was stirred for 3 days. The mixture was concentrated, diluted with ethyl acetate, washed with 1 N HCl and brine solution and was dried over magnesium sulfate. Filtration and evaporation afforded a residue, which was purified by silica gel chromatography using a Biotage column (40 s) to give N-[(2-ethyl-6-methylphenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester as a white foam (79 mg, 62%). ES-HRMS m/e calcd for C28H29F3NO4 (M+Na) 537.1974. found 537.1972. d. Preparation of N-[(2-ethyl-6-methylphenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]=O)=[N+:9]=[N-:10].[Cl:19][C:20]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[C:23]([Cl:31])[C:21]=1[NH2:22]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[N:22]/[C:21]1[C:20]([Cl:19])=[CH:26][C:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][C:23]=1[Cl:31])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Reactant: CS(=O)(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(Cl)c(/N=C/c2cnccc2N=[N+]=[N-])c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (1.7 mL, 12.6 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (621 mg, 4.2 mmol) and 2,6-dichloro-4-(methylsulfonyl)aniline (1 g, 4.2 mmol) in DCM (15 mL) under nitrogen. Titanium tetrachloride (1 M, 2.5 mL, 2.5 mmol) was then added and the resulting mixture was stirred for 1 hour, warmed to room temperature, and stirred for an additional 4 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH2:11]>C1COCC1>[Br:1][C:2]1[C:3]([NH:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: C1CCOC1
Product: CNc1nc(Cl)ncc1Br
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
5-Bromo-2,4-dichloro-pyrimidine (2.41 g, 10.6 mmol) is slowly treated with methylamine (8 M in EtOH, 3.3 mL) in THF (15 mL) at about −20° C. After stirring for 30 minutes at about −20° C., the reaction mixture is partitioned between CHCl3 and saturated NaHCO3. The aqueous layer is extracted with additional CHCl3 twice and the combined organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography (SiO2, EtOAc/Hexane=3/7) to give 1.76 g (75%) of (5-bromo-2-chloro-pyrimidin-4-yl)-methylamine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
3-Fluoro-4-nitrophenol (10 g, 63.65 mmol) was dissolved in N,N-dimethylformamide (120 ml), and then sodium hydride (2.68 g, 67.00 mmol, 60% in oil) was added and the mixture was stirred for 15 minutes at room temperature under a nitrogen atmosphere. After adding benzyl bromide (7.6 ml, 63.65 mmol), the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water was added to the reaction solution, and the precipitated crystals were filtered out, washed with water and dried by aspiration to obtain the title compound (16.06 g, quant.) as crude light yellow crystals. These were used without further purification for the following reaction.