Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[S:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:42])[F:41])=[CH:32][N:33]=1>C(#N)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[S:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([F:43])([F:41])[F:42])=[CH:32][N:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: FC(F)(F)c1ccccc1-c1cnc(CBr)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: O=c1n(Cc2ncc(-c3ccccc3C(F)(F)F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
40 mg (0.13 mmol) of the compound from Example 5A were dissolved in 7 ml of acetonitrile, and 66 mg (0.20 mmol) of cesium carbonate and 42 mg (0.13 mmol) of the compound from Example 89A were added. The mixture was stirred at 80° C. for 1 h. For work-up, the mixture was cooled to RT, diluted with 5 ml of methanol and filtered. The filtrate was concentrated under reduced pressure and the crude product was then purified chromatographically [Method 19]. This gave 47 mg (66% of theory) of the target compound.
Reaction SMILES: C(N1C(=O)C(N[C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])(C)C(=O)NC1=O)C.[NH2:26][C:27]1([CH2:39][CH3:40])[C:32](=[O:33])[N:31]([CH:34]([CH3:36])[CH3:35])[C:30](=[O:37])[NH:29][C:28]1=[O:38]>>[CH2:39]([C:27]1([NH:26][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])[C:32](=[O:33])[N:31]([CH:34]([CH3:36])[CH3:35])[C:30](=[O:37])[NH:29][C:28]1=[O:38])[CH3:40]
Reactant: CCC1(N)C(=O)NC(=O)N(C(C)C)C1=O
Reactant: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Product: CCC1(NC(=O)c2cc(F)c(F)c(F)c2F)C(=O)NC(=O)N(C(C)C)C1=O

Procedure:
Compound 20g was prepared by the same method described for 20f using 5-amino-5-ethyl-1-isopropylbarbituric acid (0.37 g, 2 mmol). The crude 5-ethyl-1-isopropyl-5-(tetrafluoro-benzamido)barbituric acid (20g) was obtained as white crystals and did not require further purification.
Reaction SMILES: [OH2:1].[OH:2][C:3]1([C:8]#[N:9])[CH2:7][CH:6]=[CH:5][CH2:4]1>C(O)(=O)C>[OH:2][C:3]1([C:8]([NH2:9])=[O:1])[CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: O
Reactant: N#CC1(O)CC=CC1
Solvent: CC(=O)O
Product: NC(=O)C1(O)CC=CC1
Reaction time: 8 h

Procedure:
To 5 ml. of a solution prepared by mixing one part of water and 9 parts of glacial acetic acid, and then cooling to 0°-10° C., is added 300 mg. of 1-hydroxy-3-cyclopentene-1-carbonitrile. To this is then added 5 ml. of a solution prepared by saturating glacial acetic acid with gaseous hydrogen bromide and cooling to 0°-10° C. The resulting mixture is allowed to stand at room temperature overnight. It is then evaporated to dryness in vacuo, and the residue is partitioned between ethyl acetate and 5% sodium bicarbonate solution. The ethyl acetate layer is separated, and then dried using anhydrous magnesium sulfate. Removal of the ethyl acetate by evaporation in vacuo affords 1-hydroxy-3-cyclopentene-1-carboxamide.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[NH2:17])(=[O:4])=[O:3].[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:23]=[CH:22]2>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:17][S:29]([C:24]1[CH:23]=[CH:22][C:21]2[C:26](=[CH:27][CH:28]=[C:19]([F:18])[CH:20]=2)[CH:25]=1)(=[O:30])=[O:31])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1N
Reactant: O=S(=O)(Cl)c1ccc2cc(F)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (cf. Example 20c, 0.27 g) and 6-fluoro-naphthalene-2-sulfonyl chloride (0.148 g; cf. Brown, George Robert; Stokes, Elaine Sophie Elisabeth; Waterson, David; Wood, Robin. WO 9706802) in dichloromethane (1.0 ml) was added DMAP (0.037 g). The reaction mixture was stirred at rt for 2 h and directly chromatographed on silica gel using heptane/ethyl acetate as eluent to produce the title compound (0.098 g) as a colorless foam. MS (ISP): 457.3 (M+H)+
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[Cl:40][CH:41]=[CH:42][CH2:43]Cl>CN(C=O)C>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[N:32]([CH2:43][CH:42]=[CH:41][Cl:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1Br
Reactant: ClC=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1Br
Temperature: 25 °C
Yield: 94.6 %

Procedure:
NaH (107 mg, 2.69 mmol, 60% in oil) was added to a solution of 212 (1.3 g, 2.24 mmol) in DMF (15 mL) at 0° C. 1,3-Dichloropropene (414 mg, 3.36 mmol, mixed isomers) was added and the mixture was allowed to warm to room temperature over 12 h. The DMF was evaporated under reduced pressure and the residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with H2O, brine, then dried and evaporated. The residue was purified by chromatography on silica gel, eluting with petroleum ether/EtOAc (4:1) to give tert-butyl 1-bromo-7-[(dibenzylamino)sulfonyl]-2-naphthyl(3-chloro-2-propen-1-yl)carbamate (213) (1.39 g, 95%) as a yellow foam: 1H NMR (CDCl3) (mixture of rotamers and E and Z forms) δ 8.86 (s, 1H), 7.97-7.91 (m, 1H), 7.89-7.82 (m, 2H), 7.51-7.31, 7.26-7.16 (2 m, 7H), 7.13-7.06 (m, 4H), 6.14-6.01 (m, 2H), 4.64-4.48, 4.02-3.90 (2 m, 2H), 4.43 (s, 4H), 1.56, 1.33 (2 s, 9H). HRMS (FAB) calcd. for C32H3279Br35ClN2O4S (M) 655.1033, found 655.1032.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:43][O:44][NH:45][CH3:46]>CN(C=O)C>[CH3:43][O:44][N:45]([CH3:46])[C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: CNOC
Reactant: Nc1nccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nccnc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-aminopyrazine-2-carboxylic acid (1 g, 7.2 mmol) in DMF (15 ml) is added EDC hydrochloride (1.7 g, 8.6 mmol), HOBt (1.16 g, 8.6 mmol), diisopropylethylamine (3.08 ml, 18 mmol) and N-methoxy-N-methylamine hydrochloride (0.84 g, 8.6 mmol), and the resulting solution is stirred at room temperature for 15 hours. The reaction is concentrated in vacuo, and sat. aq. NaHCO3 (50 ml) is added to the residue. The product is extracted into EtOAc (3×60 ml), washed with sat. aq. NaCl (2×50 ml), dried (MgSO4) and concentrated in vacuo to afford a yellow residue. Purification by flash chromatography (SiO2, 0-5% MeOH in DCM) yields 3-amino-pyrazine-2-carboxylic acid methoxy-methylamide as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2C(=CC=[CH:8][CH:9]=2)C=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][C@H:15]1[CH2:39][NH2:40])(=[O:13])=[O:12].[C:41]1([CH3:49])[C:42]([CH:47]=O)=[CH:43][CH:44]=[CH:45][CH:46]=1.Cl[Sn]Cl.[BH3-]C#N.[Na+]>CO>[CH3:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:49][NH:40][CH2:39][C@H:15]1[N:14]([S:11]([C:2]2[CH:3]=[CH:8][C:9]3[C:10](=[CH:10][CH:1]=[CH:2][CH:3]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:18][C@H:17]([SH:19])[CH2:16]1
Reactant: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: Cc1ccccc1C=O
Agent: Cl[Sn]Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1CNC[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
250 mg (0.56 mmol) (2S,4R)—C-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methylamine and 58 μl (0.5 mmol) o-tolualdehyde in 1 ml MeOH were treated with a solution of 57 mg (0.3 mmol, 0.6 eq) SnCl2 and 38 mg (0.6 mmol, 1.2 eq) NaBH3CN in 1 ml MeOH at room temperature and subsequent cleavage of the protecting group (Method 3) gave (3R,5S)-5-[(2-methyl-benzylamino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol as white solid, mp 122° C., MS: 427 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[Cl:29])[CH3:37])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1ccccc1Cl
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CC(Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccccc1Cl

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 1-(2-chloro-phenyl)-ethanol. MS (ESI) m/z 519.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]([NH:25][NH2:26])(=O)[CH:21]([CH3:23])[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:20]([CH:21]([CH3:23])[CH3:22])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CC(C)C(=O)NN
Solvent: CCO
Product: CC(C)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione is heated in ethanol with isobutyric acid hydrazide and the resulting product heated to 250° C. to give 8-chloro-1-isopropyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: N1[NH:2][C:3](=[O:7])[CH:4]=[CH:5]C=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])=[CH:11][CH:10]=1.N>>[CH3:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:18][C@H:16]1[CH2:17][C@@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([N:2]2[CH2:5][CH2:4][C:3]2=[O:7])=[CH:10][CH:11]=1
Reactant: O=c1cccn[nH]1
Reactant: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: N
Product: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(N2CCC2=O)cc1

Procedure:
The title compound was prepared using the procedure described in Example 35B substituting azetidin-2-one for pyridazin-3(2H)-one and substituting the product from Example 35A for the product from Example 34F. 1H NMR (300 MHz, CD3OD) δ 0.98-1.04 (m, 1H), 1.08-1.15 (m, 1H), 1.34 (d, J=6 Hz, 3H), 1.35 (m, 1H), 1.59-1.72 (m, 1H), 1.94-2.04 (m, 3H), 2.18-2.29 (m, 1H), 2.75 (q, J=6 Hz, 1H), 2.98-3.07 (m, 1H), 3.08 (t, J=6 Hz, 2H), 3.16-3.26 (m, 1H), 3.32-3.36 (m, 1H), 3.52-3.62 (m, 1H), 3.65 (t, J=6 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 7.30 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 299 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[C:10](=O)[C:11]4[CH:12]=[CH:13][C:14](Br)=[CH:15][C:16]=4[C:17](=O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26].I.O.II>C(O)(=O)C>[CH3:26][C:5]1([CH3:27])[C:6]2[C:7](=[CH:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:18]=3[CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:23]2[C:4]1=[CH:3][CH:2]=[CH:25][CH:24]=2
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1cc(Br)ccc1C3=O
Agent: I
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)c2ccccc2-c2cc3cc4ccccc4cc3cc21
Reaction time: 48 h
Yield: 58.6 %

Procedure:
2,9-dibromo-13,13-dimethyl-6H-indeno[1,2-b]anthracene-6,11(13H)-dione (19 g, 0.058 mol) was dissolved in acetic acid (200 ml), and added with 57% HI (50 ml), followed by reflux-stirring for 48 hours. After the reaction was completed, the resultant solution was added with distilled water (500 ml). The produced solid was filtered and dissolved in toluene (200 ml) and iodine (4.56 g, 0.018 mol) was added thereto, followed by reflux-stirring for 3 hours. After the reaction was completed, through extraction and column chromatography, 13,13-dimethyl-13H-indeno[1,2-b]anthracene (10 g, yield 54%) was obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=1>>[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:18]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: COC(=O)CCc1cccc(CNS(=O)(=O)c2ccccc2)c1

Procedure:
The title compound was prepared following the procedure described in Step B of Example 3 from benzenesulfonyl chloride and 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, prepared of Preparation 44. 1H NMR (400 MHz, CDCl3)δ7.84 (d, 2H), 7.58-7.47 (m, 3H), 7.17 (m, 1H), 7.06 (m, 1H), 6.99 (m, 2H), 4.62 (m, 1H), 4.10 (d, 2H), 3.84 (s, 3H), 2.84 (t, 2H), 2.53 (t, 2H).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N+:13]([O-])=O.[NH4+].[Cl-]>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[NH:13][CH:2]=[CH:1]2
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Vinylmagnesium bromide (1 M in THF, 681.5 mL) was added to a solution of 1-bromo-4-fluoro-2-nitrobenzene (D39) (52.0 g) in anhydrous THF (500 mL) dropwise at −78° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (3×200 mL). The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography on silica gel to afford 7-bromo-4-fluoro-1H-indole (D40) (20.0 g) as a white solid.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][N:22]2[C:23]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=3)=[CH:24][N:20]=[CH:21]2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cn2cncc2Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 1-trityl-4-(4-Cyanobenzyl)-imidazole (1.99 g, 4.64 mmol) in CH2Cl2 (9.3 mL), Hunigs base (1.62 mL, 9.28 mmol) and the product from step B (1.0 g 4.64 mmol) at −78° C. was added trifluoromethanesulfonic anhydride (0.78 mL, 4.64 mmol). After 45minutes the reaction was allowed to warm to room temperature. The solvent was evaporated and the residue was dissolved in methanol (50 ml) and heated at reflux for 1 hour, cooled and evaporated to dryness. The residue was partitioned between sat. aq. NaHCO3 solution and CH2Cl2. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 3% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH3:22])=[NH:10])[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](OB(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C>>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:7]=[CH:6][N:5]=1)=[NH:10]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1cc(Br)ccn1
Reactant: OB(O)Oc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(OC)c1CNC(=N)Nc1cc(-c2ccc(F)cc2)ccn1
Temperature: 110 °C
Yield: 55.3 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.160 g (0.438 mmol) N-(4-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine, 0.091 g (0.657 mmol) (4-fluorophenyl)boric acid, 0.139 g (1.314 mmol) sodium carbonate, and 0.035 g (0.031 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 18.5 hr at 110° C. under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 106.5 mg (0.242 mmol, 55%) pure N-(2,6-dimethoxybenzyl)-N′-[4-(4-fluorophenyl)pyridin-2-yl]guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)=[O:4].[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(#N)C>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])=[CH:7][CH:6]=3)=[O:4])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccc(C(=O)CBr)cc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCCc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A solution of N-(2-[4-bromoacetylphenyl]ethyl)-4-methylphenylsulphonamide (485 mg) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture was stirred for 18 hours. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane. On evaporation of the eluant fraction crystallisation occured. These crystals on filtration and washing with dichloromethane gave the title compound, 230 mg, as an off-white solid: m.p. 133°-135° C.; NMR(d6DMSO) δ 8.14(2H,bd), 7.90(2H,d), 7.65(2H,d), 7.59(1H,t), 7.35(2H,d), 7.29(2H,d), 6.81(2H,d), 3.37(2H,s), 3.33(4H,t), 2.98(2H,q), 2.76(2H,t), 2.63(4H,t), 2.38(3H,s); m/e 479(M+H)+ ; calculated for C26H30N4O3S: C, 65.2; H, 6.3; N, 11.7; found. C 65.0; H, 6.3; N, 11.4%.
Reaction SMILES: CC(OC([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]=[N:9]1)=O)(C)C.[ClH:16].CCOCC>O1CCCC1>[ClH:16].[NH:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1N=CC[C@H]1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)[C@@H]1CC=NN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
To a 2000 ml round bottom flask was added (5S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (34 g, 159 mmol) in tetrahydrofuran (THF) (600 mL), followed by HCl (397 mL, 1587 mmol) (4 M in dioxane). The mixture was stirred at room temperature for 18 hours, and then ether (600 mL) was added. After stirring for 5 min, the mixture was allowed to stand for 10 min and then the organic solvents were decanted. The solid was collected by filtration and dried under high vacuum to provide (5S)-4,5-dihydro-1H-pyrazole-5-carboxylic acid, hydrochloride (22.4 g, 149 mmol, 94% yield) as a pale yellow solid. 1H NMR (400 MHz, METHANOL-d4): δ ppm 3.40-3.66 (m, 2H) 4.75-4.84 (m, 1H) 8.05-8.13 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNS(=O)(=O)c2ccccc2)no1

Procedure:
Method as for preparation 6 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (205 mg, 0.58 mmol) and benzenesulphonylchloride (75 μl, 0.58 mmol) as starting materials.
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14]Br)[CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>CN(C=O)C>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][O:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCN(CCON2C(=O)c3ccccc3C2=O)C1
Reaction time: 5 h
Yield: 47.6 %

Procedure:
To a suspension of (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (6.90 g, 20 mmol) and triethylamine (4.04 g, 40 mmol) in DMF (30 ml) was added N-hydroxyphthalimide (3.26 g, 20 mmol). The mixture was stirred for 5 h, filtered and the solvent was evaporated from the filtrate in vacuo. The residue was dissolved in dichloromethane (50 ml) and the resulting mixture washed with 10% aqueous potassium carbonate (3×20 ml) and water (20 ml). The solvent was evaporated in vacuo and the residue crystallised from absolute ethanol (25 ml). The precipitate was collected, washed with cold absolute ethanol and dried in vacuo to give 3.3 g of (R)-1-(2-((phthalimido)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:31]>O1CCOCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH2:31])=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(N)=O)c3)C(C)(C)C2=O)cc1
Temperature: 130 °C

Procedure:
To a solution of 250 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 5 mL of dioxane are added 6.5 mL of a 7N solution of ammonia in methanol. The reaction mixture is heated by microwave at 130° C. for 3 hours and concentrated under reduced pressure. The residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 54 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)urea, the characteristics of which are as follows: