Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:30][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:32][CH:31]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: Cc1cnc(Cl)nc1Nc1ccc(F)c(Cl)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Nc1ccc(F)c(Cl)c1
Yield: 78 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-N-(3-chloro-4-fluorophenyl)-5-methylpyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 78% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). MS (ESI): 440.4 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH3:15])[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31]([NH:1][C@H:2]2[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH3:15])[C:3]2=[O:16])=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CC=C[C@@H](c2ccccc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 18.4 %

Procedure:
To a solution of (3S,7S)-3-amino-1-methyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (1f) (120 mg) in DCM (6 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (135 mg), HOBt-hydrate (186 mg), EDAC.HCl (160 mg) and N-methyl morpholine (92 mg). The reaction mixture was stirred 1 h at 0° C. and 2.5 h at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1% MeOH/DCM) to afford the title compound as an off-white solid (45 mg, 19%). 1H NMR (300 MHz, CDCl3) δ 1.41 (d, 3H), 2.18-2.29 (m, 1H), 2.54 (s, 3H), 2.79-2.87 (m, 1H), 3.55 (s, 2H), 4.47-4.57 (m, 1H), 5.45-5.54 (m, 1H), 5.86 (m, 2H), 6.14-6.19 (m, 1H), 6.29 (bd, 1H), 6.69-6.76 (m, 1H), 6.84 (bd, 2H), 7.22-7.45 (m, 5H). MS APCI, m/z=464 (M+Na). LC/MS 2.52 min., Method A.
Reaction SMILES: [CH2:1]1[NH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][NH:11][CH2:12][CH:2]12.CCN(CC)CC.[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])OCC1CN2C(CS(=O)(=O)CC2)CN1)([CH3:23])[CH3:22]>ClCCl>[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])[O:8][CH2:7][C@H:5]1[CH2:4][N:3]2[CH2:9][CH2:10][NH:11][CH2:12][CH:2]2[CH2:1][NH:6]1)([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCC1CN2CCS(=O)(=O)CC2CN1
Reactant: OC[C@H]1CN2CCNCC2CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN2CCNCC2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting (3R)-octahydro-2H-pyrazino[1,2-a]pyrazin-3-ylmethanol (D89, 528 mg, 3.08 mmol) was dissolved in 20 mL of dichloromethane and treated with Et3N (1.29 mL, 9.25 mmol) and TDBMSCl (929.5 mg, 6.17 mmol). The reaction was stirred at room temperature overnight and then for additional 24 h. It was checked by UPLC/MS, which showed conversion to product: peak at 0.47 min, m/z=286 (M+1), 172 (M-TBDMS+1). The crude was purified by flash chromatography (silica, CH2Cl2: (0.5 M NH3 in MeOH) 98:2 to 85:15). The residue obtained evaporating the fractions containing the product was dissolved in dichloromethane:MeOH 90:10 and the insoluble material was filtered away. The solution was evaporated to give 638 mg of the target product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](C2C=CC=CC=2)[N:30]=1.BrC1C=CC=C(Br)N=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: Brc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and a mixture of (2-bromo-6-phenyl-pyridine and 2,6-dibromo-pyridine). The products were purified on silica but not separated from one another. The mixture was used in the next step.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([SH:16])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([CH3:9])[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:11]=1
Reactant: Nc1ccc(I)cc1
Reactant: Cc1cccc(S)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cccc(Sc2ccc(N)cc2)c1
Yield: 90.1 %

Procedure:
The general procedure in example 39 was followed. 4-Iodoaniline (219 mg, 1.0 mmol), m-thiocresol (119 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 4-(3-tolyl)sulfanylaniline (194 mg, 90% yield) as pale yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=4/1). Rf=0.4 (hexane/ethyl acetate=4/1). 1H NMR (CDCl3, 300 MHz) δ 7.28 (dt, 2 H, J=7.5 Hz, 0.9 Hz), 7.08 (t, 1 H, J=7.8 Hz), 6.91 (t, 3 H, J=7.5 Hz), 3.71 (brs, 2 H), 2.26 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 138.8, 138.1, 136.2, 128.9, 128.1, 126.4, 124.6, 117.5, 116.1, 100.0, 21.8. IR (neat, cm−1) 3460 (broad), 3377 (broad), 3211, 3051, 3027, 2919. MS (EI) m/z (relative intensity) 219 (100), 92 (80). HRMS (EI), Cald. for C13H13NS 215.0769. Found 215.0766.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][C:8]3[N:9]2[C:12]([CH3:15])=[N:13][N:14]=3)=[CH:4][CH:3]=1.[SH:22][C:23]1[CH:24]=[C:25]([C:29]2([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][C:12]1[N:9]2[C:10]3[C:5]([C:6]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][C:8]2=[N:14][N:13]=1)=[CH:4][CH:3]=[C:2]([S:22][C:23]1[CH:24]=[C:25]([C:29]2([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1)[CH:11]=3
Reactant: OC1(c2cccc(S)c2)CCOCC1
Reactant: Cc1nnc2cc(-c3ccccc3)c3ccc(I)cc3n12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnc2cc(-c3ccccc3)c3ccc(Sc4cccc(C5(O)CCOCC5)c4)cc3n12
Temperature: 70 °C

Procedure:
5u (100 mg, 0.26 mmol), 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-ol (5v, 65 mg, 0.31 mmol), iPr2NEt (0.1 mL, 0.52 mmol), Pd2dba3 (6 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.01 mmol) were dissolved in 1,4-dioxane (4 mL) and degassed with N2 for 5 minutes. The mixture was heated to 70° C. until no starting material was seen by tlc analysis. The reaction was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography to give the desired product, 5y.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][C:11](I)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>[Cu]I.O1CCCC1.CCN(CC)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](/[CH:24]=[CH:23]/[C:22]([O:26][CH3:27])=[O:25])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Fc1ccc(-c2ncc(I)nc2-c2ccc(F)cc2)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2,3-bis(4-fluorophenyl)-5-iodopyrazine (400 mg, 1.02 mmol, 1.00 equiv), methyl acrylate (1.8 g, 20.93 mmol, 20.62 equiv), CuI (193 mg, 1.02 mmol, 1.00 equiv), Pd(PPh3)Cl2 (285 mg, 0.41 mmol, 0.40 equiv), and tetrahydrofuran/Et3N (2/1 mL) was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated in vacuo, and purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:40)) resulting in 120 mg (28%) of (E)-methyl 3-(5,6-bis(4-fluorophenyl)pyrazin-2-yl)acrylate as a grey solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:11][NH2:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C[O:14][C:15](=O)[N:16]=[C:17](SC)[C:18]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[F:42])=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][NH:8][C:7]=1[N:11]1[C:15](=[O:14])[NH:16][C:17]([CH:18]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=2[F:42])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[N:30]=[C:29]([CH3:31])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[N:12]1)=[O:5])[CH3:2]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: CCOC(=O)c1c[nH]nc1NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.9 %

Procedure:
A solution of 0.140 g of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester, 0.236 g of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 1d) and 0.209 ml of triethylamine in 6 ml of DMF was heated at 85° C. for 15 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in 7 ml of methanol, and then 0.251 g of sodium cyanotrihydroborate, 0.086 ml of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (0.152 g) as a light green solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C:7]1([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:4].CCN(CC)CC.[CH:28]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH2:30][CH2:29]1>C(Cl)Cl>[CH:28]1([CH2:31][S:32]([N:16]2[CH2:17][CH2:18][N:13]([C:7]3([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:19])([F:1])[F:20])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:14][CH2:15]2)(=[O:34])=[O:33])[CH2:30][CH2:29]1
Reactant: O=C(NCC1(N2CCNCC2)CCCCC1)C(F)(F)F
Reactant: O=S(=O)(Cl)CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1(N2CCN(S(=O)(=O)CC3CC3)CC2)CCCCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring ice-cold solution of 14 (10.0 g, 34.09 mmol) and Et3N (14.2 mL, 102.27 mmol) in CH2Cl2 (200 mL) was slowly added 1-cyclopropylmethylsulfonyl chloride (5.27 g, 34.09 mmol). The mixture stirred at ambient temperature under an atmosphere of nitrogen for 3 h. The mixture was washed with 2 N NaOH (50 mL), 2 N HCl (50 mL), H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford N-((1-(4-(cyclopropylmethylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,2,2-trifluoroacetamide (18) as an off-white solid (14.00 g, quantitative): MS (ESI+) m/z 412.
Reaction SMILES: C([Li])CCC.[I-].[CH3:7][P+:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:27][C:28]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](OC)=[O:31]>CCCCCC.C1COCC1>[OH:27][C:28]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](=[O:31])[CH:7]=[P:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(C)c1O
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
206.8 ml (330.9 mmol) of a 1.6 molar n-butyllithium solution in n-hexane are slowly added to 97.3 g (240.7 mmol) of methyltriphenylphosphonium iodide in 800 ml of absolute THF under argon. The mixture is stirred at room temperature for 3 h. Subsequently, 20.0 g (120.3 mmol) of methyl 2-hydroxy-3-methylbenzoate in 200 ml of absolute THF are added dropwise to the reaction mixture. The mixture is stirred at 60° C. for 3 h. After cooling to room temperature, the precipitated lithium iodide is filtered off. The filtrate is concentrated in vacuo, and the residue is recrystallized from methanol. 27 g (56% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[CH2:7]1)(=[O:4])=[O:3].[OH-].[Na+].I[CH3:34]>CN(C)C=O>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([CH3:34])[C:26]2=[O:30])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1CCN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (0.80 g) in N,N-dimethylformamide (10 ml) was added sodium hydroxide (78 mg) under ice-cooling and the mixture was stirred at the same temperature for 20 minutes. To a solution was added iodomethane (0.34 ml) and the mixture was stirred at 30° C.-50° C. for 1 hour. The reaction mixture was poured into ice-water (30 ml) and extracted twice with ethyl acetate (30 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:l,V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(3-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.78 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[S:28])[NH:6]2.[C:29](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[N:8]=[C:7]3[C:3]([NH:4][C:5]([S:28][CH3:29])=[N:6]3)=[C:2]([NH2:1])[N:10]=2)=[N:12]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=S)[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2[nH]1
Temperature: 70 °C
Reaction time: 48 h
Yield: 17.4 %

Procedure:
100 mg (0.255 mmol) of the compound from example 28 were dissolved in 5 ml of dimethylformamide, and 49 mg (0.357 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 18 μl (0.291 mmol) of iodomethane were added and the mixture was stirred at RT for 48 h. The mixture was concentrated and the residue was taken up in water and acidified with acetic acid. A solid precipitates out, which was filtered off and washed with water. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 18 mg of the title compound were obtained (17% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl>[CH3:54][S:55]([NH:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:20][CH:21]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:11]1)(=[O:57])=[O:56]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
A solution of 0.25 g of tert-butyl 3-{2-[2-(2-aminoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 12 ml of dichloromethane is admixed at room temperature with a solution of 0.12 ml of triethylamine in 1 ml of dichloromethane. Subsequently, a solution of 0.034 ml of methanesulphonyl chloride in 1 ml of dichloromethane is added dropwise. After stirring for 2 hours, the reaction mixture is diluted with dichloromethane, washed with 1M aqueous potassium bisulphate solution (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.07 (1:2 EtOAc-heptane); Rt=5.78.
Reaction SMILES: CC(O)=O.Cl[S:6]([C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:22])[CH:10]=1)(=O)=O.Cl[Si](Cl)(C)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH:42](O)[CH3:43])[CH:37]=2)=[CH:32][CH:31]=1>CCOC(C)=O.[Zn]>[CH3:22][C:11]1[CH:10]=[C:9]([S:6][CH:42]([C:38]2[CH:37]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=3)[CH:41]=[CH:40][CH:39]=2)[CH3:43])[CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(SC(C)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
Zinc (229 mg, 3.50 mmol) was added to EtOAc (10 mL) followed by AcOH (115 μM, 2.00 mmol) and ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (293 mg, 1.00 mmol). After 2 hours, dichlorodimethylsilane (258 mg, 2.00 mmol) was added followed by 1-[4′-(trifluoromethyl)-3-biphenylyl]ethanol (266 mg, 1.00 mmol) and the mixture stirred for a further 1 hour and then heated at 80° C. for 5 hours. The mixture was then cooled, diluted with EtOAc and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, water and brine, and then reduced. Purification by Biotage™ chromatography (silica) eluting with petrol:EtOAc (9:1) afforded the title compound as a colourless oil (238 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)[C:35]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (59 mg, 0.22 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (39 mg, 0.22 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid (55 mg, 0.19 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 20 min. The reaction mixture was then treated with 2-aminothiazole (41 mg, 0.41 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/1 methylene chloride/methanol) to afford impure 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide as an orange foam. The impure foam was treated with a solution of hexanes/ethyl acetate (5 mL, 1:3), and a precipitate formed. The reaction mixture was placed in the freezer for 15 h, and the solid was collected by filtration to afford 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide (26 mg, 37%) as a pale orange solid: mp 213-215° C.; EI-HRMS m/e calcd for C22H23N3OS (M+) 377.1562, found 377.1564.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].CCN(C(C)C)C(C)C>C(C#N)(C)=O>[Cl:11][C:4]1[CH:3]=[C:2]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([I:12])[CH:14]=2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Reactant: NCc1cccc(I)c1
Agent: CC(=O)C#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Cl)cc1NCc1cccc(I)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
To a solution of 4,6-dichloronicotinamide (296 mg, 1.55 mmol) in AcCN (3 mL) was added 3-iodobenzylamine (396 mg, 1.70 mmol) and DIPEA (0.383 mL, 2.32 mmol). After stirring at 80° C. for 15 h, the mixture was concentrated and added water, the resulting precipitate was collected by filtration to give 6-chloro-4-(3-iodobenzylamino)nicotinamide (588 mg).