Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[NH:29][CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:29]([C:28]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:27]=3[F:26])[CH3:30])=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: CNc1ccc(F)cc1F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccc(F)cc1F
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro) benzenesulfonamide (Intermediate 8), and 2,4-difluoro-N-methylaniline, the title compound was isolated as a yellow solid in 77% yield (92% purity by HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1B(O)O.N>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Agent: N
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC3
Yield: 50.2 %

Procedure:
The title compound (55.9 mg, 50%) was prepared by the method of Example 89 Step C from tert-butyl (±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (94 mg, 0.25 mmol) and 2,4-dichlorophenylboronic acid (95 mg, 0.5 mmol) as a white amorphous solid. MS (CI, NH3): 445 (base, M+H).
Reaction SMILES: CO[CH:3]([O:22]C)[C:4](=O)[CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].[C:24]([OH:27])(=[O:26])[CH3:25]>O1CCCC1>[O:26]1[CH2:5][CH2:4][CH2:3][CH2:25][CH:24]1[O:27][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:4]([CH:3]=[O:22])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18]
Reactant: COC(OC)C(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Reactant: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C=O)=CCCC(C)=CCOC1CCCCO1

Procedure:
Following the procedure stated in Example 2-(1), 5.8 g of (E)-4-methyl-6-(2'-tetrahydropyranyloxy)-4-hexen-1-yltriphenylphosphonium iodide was treated with n-buthyllithium in 30 ml of anhydrous tetrahydrofuran. Then, the resultant was treated with 3.2 g of 1,1-dimethoxy-6,10,14-trimethyl-5,9,13-pentadecatrien-2-one prepared by the process stated in Referential example 7. The resulting oil was treated with 40 ml of 50% acetic acid to yield 4.2 g of 7-formyl-3,11,15,19-tetramethyl-2,6,10,14,18-eicosapentaen-1-ol tetrahydropyranyl ether. The product was reduced with 150 mg of sodium borohydride and treated with p-toluenesulfonic acid in methanol in the same manner as stated earlier, and purified by the silica gel column chromatography to yield 1.6 g of the desired product. This was a mixture of the (E,E,E,E), (E,Z,Z,E), (E,Z,E,E) and (E,E,Z,E) isomers.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.[Cu].CN(CCN(C)C)C>[I:1][C:2]1[N:3]=[C:4]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[I:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[N:5][CH:6]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: OB(O)c1ccccc1
Agent: [Cu]
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: Cc1nc(I)cn1-c1ccccc1
Product: Cc1ncc(I)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40 %
Yield: 35 %

Procedure:
4-Iodo-2-methyl-1H-imidazole (1.0 g, 4.8 mmol) was dissolved in 30 mL of THF. Copper TMEDA catalyst (447 mg, 0.96 mmol, Aldrich) and then phenylboronic acid (0.41 g, 3.35 mmol) were added. Oxygen gas was bubbled into the reaction mixture for 20 min, then the mixture was stirred at room temperature for 90 min. An additional 0.21 g of phenylboronic acid was added followed by an additional 20 min of oxygen gas bubbling and 75 min of stirring at room temperature. An additional 0.21 g of phenylboronic acid was added followed by an additional 20 min of oxygen gas bubbling and then stirring at room temperature for 20 h. The reaction mixture was filtered through a bed of neutral alumina, concentrated and purified by silica gel chromatography (ethyl acetate/hexanes) to give 0.55 g (40%) of 4-iodo-2-methyl-1-phenyl-1H-imidazole ((M+H)+=285) and 0.47 g (35%) of 5-iodo-2-methyl-1-phenyl-1H-imidazole.
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=O)[NH:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[CH:21]([N:24](C(C)C)CC)(C)C>C(Cl)Cl>[C:21]([C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[N:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:6]=2[N:7]=1)#[N:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Solvent: ClCCl
Product: Cc1ccnc2c1N=C(C#N)c1cccnc1N2C1CC1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
Trifluoromethanesulfonie anhydride (5.02 g, 17.8 mmole) was added dropwise to a cooled mixture of 3.00 g (11.3 mmole) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, 2.32 g (18.0 mmole) of diisopropylethylamine, and 45 mL of methylene chloride. After the addition was complete, the ice bath was removed and the mixture was stirred for one hour. Ethyl acetate (500 mL) was added and the resulting solution was washed with three 100 mL portions of water. The organic solution was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with 50% ethyl acetate/hexane) to provide 3.18 g (8.0 mmole) of the title compound as a yellow oil, suitable for the next reaction.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=3)[C:17](O)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:35]=1)([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[P:58]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([O:60][CH2:61][C:62]([NH2:65])([CH3:64])[CH3:63])=[O:59].C(N(CC)C(C)C)(C)C>CS(C)=O>[C:72]([O:71][P:58]([O:60][CH2:61][C:62]([NH:65][C:17]([C:16]1[CH:20]=[CH:21][C:22]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:32])[O:33][CH3:34])=[CH:28][CH:29]=2)=[C:14]([NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:35][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:15]=1)=[O:18])([CH3:64])[CH3:63])([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:59])([CH3:75])([CH3:74])[CH3:73]
Reactant: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Reactant: COC(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Yield: 79.4 %

Procedure:
To a suspension of the product from Example 441D (200 mg, 0.41 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (187 mg, 0.57 mmol) in DMSO (2 mL) was added the product of Example 438C (178 mg, 0.57 mmol) then N,N-diisopropylethylamine (0.220 mL, 1.10 mmol) dropwise at room temperature under N2. After 2 hours the reaction was quenche with water (20 mL) and extracted with ethyl acetate (75 mL). The organic layer was washed sequentially with water (3×) and saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give the title compound as a pale yellow amorphous solid (245 mg., 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:22])=[CH:4][N:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:38][C:39]1[CH:52]=[CH:51][C:42]2[NH:43][C:44](=[O:50])[CH2:45][CH2:46][C:47]([CH3:49])([CH3:48])[C:41]=2[CH:40]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:22][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:38][C:39]2[CH:52]=[CH:51][C:42]3[NH:43][C:44](=[O:50])[CH2:45][CH2:46][C:47]([CH3:49])([CH3:48])[C:41]=3[CH:40]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CCN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN([C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl)S(C)(=O)=O
Temperature: 120 °C

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-ethyl-methanesulfonamide (99 mg, 0.27 mmol) in Isopropyl alcohol (4 mL) was added to 10-Camphorsulfonic acid (12 mg, 0.052 mmol) and 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (56 mg, 0.27 mmol) and was heated in a Microwave vial for 90 min at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo onto Celite. Chromatography (ISCO, 12 g silica gel, 40-80% EtOAc:Hex) afforded N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-ethyl-methanesulfonamide as an off white foam (78 mg, 54%). LCMS: 535 (M+H); 1H-NMR, CDCl3: 7.91 (s, 1H), 7.74 (d, 1H, J=8.5 Hz), 7.34 (s, 1H), 7.25 (s, 1H), 7.00 (s, 1H), 6.88 (d, 1H J=8.5 Hz), 6.02 (d, 1H, J=8.2 Hz), 3.99 (m, 1H), 3.75 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 2.92 (s, 3H), 2.45 (m, 1H), 2.40 (t, 2H, J=7.0 Hz), 2.13 (t, 2H, J=7.0 Hz), 1.95 (m, 2H), 1.44 (s, 6H), 1.39 (m, 3H), 1.16 (t, 3H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=O)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH:16]([NH:25][CH3:24])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc2c1CCCC2=O
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCCc2c(Oc3cc(Cl)ccc3C#N)cccc21
Yield: 52.1 %

Procedure:
4-Chloro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxy)benzonitrile (0.22 g, 0.74 mmol), methylamine (33% in ethanol, 0.7 mL, 5.6 mmol) and sodium cyanoborohydride (60 mg, 0.81 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (40 ml) for 6 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (70 mg, 0.60 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-(5-methylamino-5,6,7,8-tetrahydronaphthalen-1-yloxy)benzonitrile fumarate (134 mg, 42%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[CH3:28][Si:29]([CH3:38])([CH3:37])[CH2:30][CH2:31][O:32][C:33]([NH:35][NH2:36])=[O:34].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:36]([NH:35][C:33]([O:32][CH2:31][CH2:30][Si:29]([CH3:38])([CH3:37])[CH3:28])=[O:34])[C:15]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:27])[CH3:2]
Reactant: C[Si](C)(C)CCOC(=O)NN
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)c1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)n(NC(=O)OCC[Si](C)(C)C)c1-c1cccc2ccccc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of 2-(Naphthalene-1-carbonyl)4-oxo-4-phenyl-butyric acid ethyl ester (1 g, 2.77 mmol) in toluene (6.5 mL) was treated with Hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (599 mg, 3.34 mmol) and p-toluene sulfonic acid (33 mg). The resulting solution was heated to reflux, with the azeotropic removal of water (Dean Stark trap), under Ar for 6 h, cooled to rt and concentrated in vacuo to afford 2-Naphthalen-1-yl-5-phenyl-1-(2-trimethylsilanyl-ethoxycarbonylamino)-1H-pyrrole-3-carboxylic acid ethyl ester (1.33 g), which was not purified, but used immediately in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:23])[CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].C([O-])(O)=O.[Na+].[ClH:38]>C(O)C.CN(C)C=O.C(N(CC)CC)C>[ClH:38].[ClH:38].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:23])[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:21][CH2:22]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCc2c(OCC(O)CN3CCNCC3)ccc(Br)c2N1
Reactant: COc1ccccc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccc(Br)c3c2CCC(=O)N3)CC1

Procedure:
2.5 Grams of 8-bromo-5-(2-hydroxy-3-piperazinylpropoxy)-3,4-dihydrocarbostyril, 2.0 g of o-bromoanisole and 2.0 g of triethylamine are mixed with 30 ml of dimethylformamide. The reaction mixture thus obtained is heated under a stream of argon gas at 120° to 130° C. for 5 hours. The reaction mixture is concentrated under a reduced pressure and to the residue thus obtained is added 30 ml of 5% NaHCO3 aqueous solution, and the organic layer is extracted with chloroform. Chloroform is removed by distillation and to the residue thus obtained are added 3 ml of concentrated hydrochloric acid, then 20 ml of ethanol are added and stirred. The crystals thus precipitated are collected by filtration to obtain 2.1 g of 8-bromo-5-{2-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.dihydrochloride in the form of colorless crystals with a melting point of 226°-228° C.
Reaction SMILES: C([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:36][CH2:35][C:30]4(OCCO4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.[OH:38][C@@H:39]([CH2:52][NH2:53])[CH2:40][O:41][C:42]1[C:50]2[NH:49][C:48](=[O:51])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1.CNC1SC(=CC2C=CC(N3CCC(=O)CC3)=CC=2)C(=O)N=1.NCC(C1C=CC(O)=C(NS(C)(=O)=O)C=1)O>>[OH:38][C@H:39]([CH2:40][O:41][C:42]1[C:50]2[NH:49][C:48](=[O:51])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)[CH2:52][NH:53][CH:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:20]=[C:16]3[S:15][C:14]([NH:13][C@@H:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:3])=[O:37])=[N:18][C:17]3=[O:19])=[CH:22][CH:23]=2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1)C(=O)OCC
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Agent: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: O=C(O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester (which was obtained in Intermediate 34) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedures of Intermediate 18, Example 1 and Example 9 as a yellowish solid; mp>270° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.70 (m, 2 H), 1.80-4.30 (m, 17 H), 6.50-6.80(m, 2 H), 6.80-7.10(m, 3 H), 7.23(d, J=8.4 Hz, 2 H), 7.37 (s, 1 H), 10.61(brs, 1 H), 11.01 (brs, 1 H); MS (ES) m/z: 320.3 ((M+2H)2+, 100%); 639.4 (MH+, 60%); HRMS Calcd. for C30H35N6O8S (MH+): 639.2231. Found: 639.2233.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=O.[NH3:14]>>[NH2:13][C:7]1[N:6]=[C:5]([C:3]([NH2:14])=[O:2])[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=1
Reactant: COC(=O)c1cc(SC)cc(N)n1
Reactant: N
Product: CSc1cc(N)nc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.099 g 6-amino-4-methylsulfanyl-pyridine-2-carboxylic acid methyl ester in 4 ml 25% aqueous ammonia was stirred at room temperature for 24 h. The solid was collected by filtration washed with water and dried to constant weight to yield 0.070 g of the title compound as white crystals melting at 158-159° C.
Reaction SMILES: C1([Mg]Br)CCCCC1.C(C1C=CC=C(C(C)C)C=1N=CC(C)C)(C)C.ClC(P)Cl.[Li:30]CCCC.Br[C:36]1[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][C:39]([CH:45]([CH3:47])[CH3:46])=[CH:38][C:37]=1[CH:48]([CH3:50])[CH3:49]>C(OCC)C.C1COCC1>[CH:48]([C:37]1[CH:38]=[C:39]([CH:45]([CH3:47])[CH3:46])[CH:40]=[C:41]([CH:42]([CH3:44])[CH3:43])[C:36]=1[Li:30])([CH3:50])[CH3:49]
Reactant: [Li]CCCC
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Agent: Br[Mg]C1CCCCC1
Agent: CC(C)C=Nc1c(C(C)C)cccc1C(C)C
Agent: PC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: [Li]c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexylmagnesium bromide (1.05 mL of a 2.0 M solution in ethyl ether, 2.1 mmol, Aldrich) was added to a solution of isobutyraldehyde 2,6-diisopropylphenylimine (0.462 g, 2.0 mmol) in THF (5 mL) at −78° C. The yellowish solution was warmed to RT, stirred for 1 h and then added to a solution of dichloromethylphosphine (0.19 mL, 2.1 mmol, Strem) in THF (5 mL) at −78° C. The solution was stirred for 10 min at −78° C., warmed to RT and stirred for 30 min. Assay by 31P-NMR (crude reaction mixture) showed the presence of a single major product (+110.4 ppm). The solution of 2,4,6-triisopropylphenyllithium was prepared by addition of BuLi (1.6 mL of a 1.6 M solution in hexanes, 2.6 mmol, Aldrich) to a solution of 1-bromo-2,4,6-triisopropylbenzene (0.63 mL, 2.5 mmol, Lancaster) in THF (8 mL) at −78° C. followed by stirring for 2 h. The solution of arylLi thus formed was added to the solution of chlorophosphine keeping both flasks at −78° C. The solution was stirred for 20 min at −78° C., warmed to RT and stirred for 30 min. Assay by 31P-NMR (crude reaction mixture) showed the presence of a single major product (−37.9 ppm). The solution was evaporated and CH2Cl2 (10 mL) was added to the residue. Filtration through a 2.2×2 cm plug of silica gel using CH2Cl2 (20 mL) and then ethyl ether (10 mL) as an eluent followed by evaporation of the solvent afforded crude product as a yellowish oil. To the crude ligand was added NiBr2(DME) (0.124 g, 0.40 mmol) and CH2Cl2 (10 mL). The red-brown solution was stirred for 1 h at RT, solution was evaporated and the residue washed with diethyl ether (3×20 mL) and hexanes (20 mL). A brown, insoluble solid (0.310 g, 107% based on Ni) was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([N:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=[N:9]1)[CH3:7]>>[CH3:5][CH:6]([N:8]1[C:12]([C:13]([Cl:3])=[O:15])=[CH:11][CH:10]=[N:9]1)[CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)n1nccc1C(=O)O
Product: CC(C)n1nccc1C(=O)Cl
Temperature: 80 °C

Procedure:
Thionyl chloride (5 ml) was added to 1-(1-methylethyl)-1H-pyrazole-5-carboxylic acid (1 g) and the reaction was heated at 80° C. for 5 h. The reaction was evaporated, then azeotroped with toluene to give title compound, 856 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]1([CH2:21][C:22](O)=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:21][C:22]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=C(O)Cc1cccc2ccccc12
Product: COC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12

Procedure:
Methyl 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate was prepared from methyl 3-aminothiophene-2-carboxylate (4.30 g, 27.3 mmol) and 2-(naphthalen-1-yl)acetic acid (3.10 g, 27.3 mmol) according to protocol A. Retention time (min)=8.738, method [7], MS (ESI) 326.1 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7](I)=[C:6]([CH3:18])[N:5]=1)[CH3:2].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].CCN(CC)CC>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:11]1([NH:10][C:8]2[C:7](/[CH:21]=[CH:20]/[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]([CH3:18])[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CC(=O)OCC
Reactant: CCNc1nc(C)c(I)c(NC2CCCCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCNc1nc(C)c(/C=C/C(=O)OCC)c(NC2CCCCC2)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a solution of 2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine (660 mg, 1.83 mmol) in DMA (7 mL) was added ethyl acrylate (458 mg, 4.58 mmol), Pd(OAc)2 (121 mg, 0.18 mmol), (o-Tol)3P (110 mg, 0.37 mmol), and Et3N (740 mg, 7.32 mmol). The mixture was then stirred at 100° C. for 12 h under N2. Standard workup and purification by column chromatography gave 411 mg (67% yield) of (E)-ethyl 3-(4-(cyclohexylamino)-2-(ethylamino)-6-methylpyrimidin-5-yl)acrylate
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][S:36][CH2:37][C:38]1[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=1)OC1C=CC=CC=1)#[N:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:25]([NH:24][C:22]#[N:23])=[N:33][CH2:34][CH2:35][S:36][CH2:37][C:38]2[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=2)[CH3:15])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Product: CN(CCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.98 g (2.6 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=585 ([M+H]+, 6), 230 (100); IR (KBr): 2164 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 160° C. with decomposition.