Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].[CH3:14][O:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:17][CH2:16][O:15][CH3:14])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: COCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO, 9849166), (1.7 g, 8.8 mmol), 2-bromoethyl methyl ether (0.85 ml, 8.85 mmol) and cesium carbonate (2.9 g, 9.0 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (125 ml) and brine (100 ml). The phases were separated, and the organic layer was dried (Na2SO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using ethyl acetate:methanol (97:3) as eluant to afford the title compound of preparation 1, 831 mg,
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[CH:12]=2)[N:9]=1.[Cl-:26].[NH4+:27]>>[ClH:26].[C:16]1([N:15]2[C:11]([CH2:10][CH:8]3[NH:9][C:3](=[NH:27])[CH2:4][CH2:5][CH2:6][CH2:7]3)=[CH:12][C:13]([C:22]([F:25])([F:24])[F:23])=[N:14]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(Cc2cc(C(F)(F)F)nn2-c2ccccc2)CCCC1
Product: Cl
Product: N=C1CCCCC(Cc2cc(C(F)(F)F)nn2-c2ccccc2)N1

Procedure:
The title material of Example 138 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:34][C:35]([NH2:37])=[O:36].[Br-]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)[CH2:34][C:35]([NH2:37])=[O:36])=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2o1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CN(CCCc1ccc(F)cc1)C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 19.1 %

Procedure:
To a stirred suspension of 6-{trans-4-[3-(4-fluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (110 mg, 0.81 mmol) in DMF (15 mL) was added NaHCO3 (140 mg, 1.6 mmol) and bromoacetamide (300 mg, 0.74 mmol). After 16 hours the reaction mixture was warmed to 50° C. After 4 hours, additional bromide (150 mg, 0.37 mmol) and NaHCO3 (31 mg, 0.37 mmol) were added, and the temperature was increased to 75° C. After 4 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organics were washed with water, saturated NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 95:4.75:0.25 CH2Cl2:MeOH:NH4OH) followed by conversion to the HCl salt gave compound 2-{[3-(4-fluorophenyl)propyl]-[4-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-cyclohexyl]amino}acetamide (60 mg, 17%), as a white solid: mp 266-270° C.; IR (KBr): 3331, 3149, 2943, 1762, 1691 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.47 (s, 1H), 9.08 (br s, 1H), 7.96 (br s, 1H), 7.73 (br s, 1H), 7.29-7.25 (m, 2H), 7.17-7.01 (m, 3H), 6.99 (s, 2H), 4.05-4.02 (m, 1H), 3.81-3.78 (m, 1H), 3.47-3.38 (m, 1H), 3.22-3.12 (m, 3H), 2.63 (t, J=8 Hz, 2H), 2.57-2.52 (m, 1H), 2.14-1.87 (m, 6H), 1.71-1.49 (m, 4H); ESI-MS (m/z): 426 [M+H]+; HPLC: method A, 5.44 minutes (98.0%); HPLC: method E, 6.50 minutes (>99%); Anal. Calcd for C24H28FN3O3.HCl: C, 61.80; H, 6.37; N, 9.01. Found: C, 61.78; H, 6.27; N, 8.80.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O>C(O)(C)(C)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[S:13][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCCC1Cl
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(Cc2nc3c(s2)CCCC3)cc1
Yield: 67.2 %

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (7.0 g), 2-chloro-cyclohexanone (7.28 g) and tert-butanol (100 mL) was heated under reflux for 3 days. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(4-nitrobenzyl)-4,5,6,7-tetrahydro-1,3-benzothiazole as pale-brown crystals (6.58 g, yield 66%) from a fraction eluted with hexane-ethyl acetate (3:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 118-119° C.
Reaction SMILES: C([N:3]([CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:13])=[CH:10][CH:9]=1)CC)C.C([Br:18])C>CO>[Br-:18].[CH:12]([C:11]1[CH:14]=[CH:15][C:8]([CH2:7][CH2:6][NH3+:3])=[CH:9][CH:10]=1)=[CH2:13]
Reactant: CCBr
Reactant: C=Cc1ccc(CCN(CC)CC)cc1
Solvent: CO
Product: C=Cc1ccc(CC[NH3+])cc1
Product: [Br-]
Reaction time: 48 h

Procedure:
All the procedures were conducted in a dry nitrogen atmosphere since the product was extremely hygroscopic. In a 100 ml two necked flask equipped with a three way cock 8.6 g of the p-diethylaminoethylstyrene as obtained in Synthesis 1 were dissolved in 35 ml of absolute methanol and then 12.7 ml of ethyl bromide were injected via a syringe. The quaternization was completed after 48 hours at 40° C. without any side reactions. After the reaction mixture was concentrated under reduced pressure, 100 ml of ethyl acetate were injected via a syringe to immediately precipitate white crystals. The crystals thus formed were separated from the solution by filtration under a dry nitrogen atmosphere, washed with ethyl acetate, dried in vacuum and recrystallized from methanol-ethyl acetate solution. The results of elemental analysis of the crystals are as follows;
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]4[CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(-c2ccc(-c3cccnc3N)cc2)c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 35.5 mg) in THF (dry) (5 mL) was added 2-chloroethanesulfonyl chloride (0.056 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(3′-methoxybiphenyl-4-yl)pyridin-2-amine (49 mg) in THF (dry) (5 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with EtOAc and dried in vacuo to give the title compound (18 mg) as a white solid.
Reaction SMILES: [S:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(O)C.CO.[NH2:29][NH2:30]>CO.CCOC(C)=O>[NH:29]([C:17](=[O:18])[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:8]2[CH:22]=[CH:23][C:5]([S:1]([NH2:2])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH2:11][CH2:12]1)[NH2:30]
Reactant: CCOC(=O)CN1CCN(Cc2ccc(S(N)(=O)=O)cc2)CC1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(S(N)(=O)=O)cc2)CC1
Yield: 90.6 %

Procedure:
To a stirred solution of 3 (110.9 g, 324.8 mmol, 1 equiv.) in 2:1 ethanol/methanol (650 mL in total, 0.5 M) was added anhydrous hydrazine (30.6 mL, 974.5 mmol, 3 equiv.). The reaction was refluxed for 16 h monitoring by TLC (1:1 MeOH/EtOAc). The reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with water (100 mL) and brine (100 mL). The aqueous layer was extracted with CH2Cl2 (3×80 mL) and EtOAc (80 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification with recrystallization in methanol gave 4 (96.3 g, 91%) as white solid. On the milligram-scale, the reaction was run in ethanol (0.06 M). 1H NMR (500 MHz, CD3OD): δ 7.85 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 3.61 (s, 2H), 3.04 (s, 2H), 2.54 (broad s, 8H). 13C NMR (126 MHz, CD3OD): δ 170.2, 142.8, 142.4, 129.7, 126.0, 61.9, 59.8, 53.0, 52.6. HRMS (ESI): found 328.1436 (M+1). calcd for C13H22N5O3S: 328.1443. m.p.: 194.5-196.0. IR (neat): 3320, 1670, 1158 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)([O-:27])=[O:26]>>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)[C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3cccc([N+](=O)[O-])c3)c12
Yield: 83 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-nitrobenzyl bromide as starting materials, the title compound was obtained in a yield of 83% as an oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:19]1([C:25]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]3[CH2:30][NH:31][CH2:32][CH2:33][N:28]3[C:27](=[O:34])[O:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.C(N(C(C)C)CC)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([N:31]2[CH2:32][CH2:33][N:28]3[C:27](=[O:34])[O:26][C:25]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:29]3[CH2:30]2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 4-fluorocinnamic acid (50 mg, 0.30 mmol) in tetrahydrofuran (1 mL) were sequentially added oxalyl chloride (46 mg, 0.36 mmol) and N,N-dimethylformamide (one drop), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. A solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (60 mg, 0.20 mmol) in tetrahydrofuran (1.5 mL) and diisopropylethylamine (0.3 mL) were sequentially added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from ethyl acetate-diisopropyl ether to obtain the title compound (32 mg, yield 36%).
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[F:15][C:16]1[CH:21]=[C:20]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)[CH:19]=[C:18]([F:37])[C:17]=1[C:38](=O)[C@@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:40].[OH-].[Na+]>ClCCCl>[F:15][C:16]1[CH:21]=[C:20]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C@H:28]3[CH2:29][CH2:30][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][CH2:33]3)[CH2:24][CH2:23]2)[CH:19]=[C:18]([F:37])[C:17]=1[CH2:38][C@@H:39]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:40]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(F)c(C(=O)[C@H](C)c4ccccc4)c(F)c3)CC2)CC1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(F)c(C[C@H](C)c4ccccc4)c(F)c3)CC2)CC1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Then, 5 ml of trifluoroacetic acid and 2.6 g (23 mmol) of triethylsilane were added to a 1,2-dichloroethane 8 ml solution of 4.1 g (9.1 mmol) of (R)-1-[2,6-difluoro-4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]phenyl]-2-phenyl-1-propanone at room temperature, followed by stirring at 60° C. for 10 hours. This reaction liquid was poured into 200 ml of a 5% sodium hydroxide solution, and after extraction with toluene, washing with water, drying, distillation of the solvent, recrystallization and purification by silica gel column chromatography were carried out to obtain 2.5 g of aimed (S)-1-[2,6-difluoro-4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]phenyl]-2-phenylpropane.
Reaction SMILES: C([Cl:4])(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:15]=[N:14][C:13]=1[C:21]#[N:22]>C(O)C>[ClH:4].[CH3:20][CH:18]([CH3:19])[CH2:17][N:16]1[C:12]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[C:21]([NH2:22])[C:13]=2[N:14]=[CH:15]1
Reactant: CC(C)Cn1cnc(C#N)c1-c1ccccc1N
Reactant: CC(=O)Cl
Solvent: CCO
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Product: Cl
Temperature: 25 °C
Yield: 23.4 %

Procedure:
A solution of acetyl chloride (0.15 mL, 2 mmol) in ethanol (2 mL) was added to a solution of 5-(2-aminophenyl)-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile (0.13 g) in ethanol (5 mL). The mixture was heated at reflux for two hours and allowed to cool to ambient temperature. The volume of the mixture was decreased to 2 mL by concentrating under reduced pressure. A solid was present, and the remaining liquid was decanted away from the solid, which was washed with diethyl ether (2×2 mL) and dried overnight in a vacuum oven at room temperature to provide 0.035 g (23% for Example 19 and Example 20 combined) of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride as a beige solid, mp>265° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[C:32]1([C:38]2[S:39][CH:40]=[C:41]([C:43](Cl)=[O:44])[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:43]([C:41]2[N:42]=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[S:39][CH:40]=2)=[O:44])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: O=C(Cl)c1csc(-c2ccccc2)n1
Product: COc1cc2c(Oc3ccc(NC(=O)c4csc(-c5ccccc5)n4)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q1 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and 2-phenyl-1,3-thiazole-4-carbonyl chloride following the general procedure reported in Preparative Example 1 Step 3. 1H NMR (400 MHz, d4-MeOD, 300K) δ 2.17 (m, 2H), 2.73 (m, 4H), 2.81 (t, J=7.4 Hz, 2H), 3.77 (t, J=4.7 Hz, 4H), 3.98 (s, 3H), 4.24 (t, J=6.0 Hz, 2H), 6.50 (d, J=5.4 Hz, 1H), 7.33 (s, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.50 (m, 4H), 7.62 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 8.01 (dd, J=12.6 Hz, J=2.5 Hz, 1H), 8.07 (m, 2H), 8.32 (s, 1H), 8.39 (d, J=5.4 Hz, 1H). MS (ES) C33H31FN4O5S requires: 614. Found: 615 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[C:23](OC)=[N:22][S:21](=[O:26])[N:20]=1>CO>[NH2:18][C:19]1[C:23]([NH:17][CH2:16][CH2:15][S:14][CH2:13][C:11]2[O:12][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)=[N:22][S:21](=[O:26])[N:20]=1
Reactant: COC1=NS(=O)N=C1N
Reactant: NCCSCc1ccc(CN2CCCCC2)o1
Solvent: CO
Product: NC1=NS(=O)N=C1NCCSCc1ccc(CN2CCCCC2)o1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 2-[(5-piperidinomethyl-2-furyl)methylthio]ethylamine (4.0 g; 15.7 mmoles) [prepared according to the procedure described in Belgian Patent No. 857,388 (U.S. Pat. No. 4,128,658)] in 25 ml of methanol was added all at once to a stirred suspension of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.31 g; 15.7 mmoles) [prepared in Step A] in 25 ml of methanol at ambient temperature. After stirring for 16 hours, the solution was evaporated under reduced pressure and the residue chromatographed by flash chromatography on 100 g of silica gel (230-400 mesh) using methanol-acetonitrile. The appropriate fractions were combined and evaporated to give 3.71 g of product. Recrystallization from 95% aqueous ethanol with charcoal treatment yielded the title compound, mp 161°-163°.
Reaction SMILES: FC(S(OS(C(F)(F)F)(=O)=O)(=O)=O)(F)F.[CH3:16][O:17][CH2:18][CH2:19]O.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:65]=[CH:66][CH:67]=1)[NH:34][C:35]1[N:40]=[C:39]([C:41]2[N:42]=[CH:43][N:44](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:45]=2)[CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[ClH:30].[Cl:30][C:31]1[CH:32]=[C:33]([CH:65]=[CH:66][CH:67]=1)[NH:34][C:35]1[N:40]=[C:39]([C:41]2[N:42]([CH2:19][CH2:18][O:17][CH3:16])[CH:43]=[N:44][CH:45]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Clc1cccc(Nc2nccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2)c1
Reactant: COCCO
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: COCCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Product: Cl
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Trifluoromethylsulphonic anhydride (0.16 ml, 0.93 mmol) was added to a solution of 2-methoxyethanol (73.7 ml, 0.88 mmol) and diisopropylethylamine (0.20 ml, 1.17 mmol) in DCM (1 ml) at −20° C. and the solution stirred for 30 minutes. This mixture was then added to a solution of 2-(3-chloroanilino)-4-(1-triphenylmethylimidazol-4-yl)pyrimidine Method 2; 300 mg, 0.58 mmol) in DCM (5 ml) at −20° C. and the reaction mixture allowed to warm and stirred for 2 hours at ambient temperature. The mixture was extracted between EtOAc and saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried and the volatiles removed by evaporation. The residue was purified by column chromatography, eluting with DCM and 7M methanolic ammonia solution (99.5:0.5 increasing in polarity to 96:4). The purified product was dissolved in either and treated with ethereal hydrogen chloride. The precipitate was collected by filtration washed with ether and dried to give the title compound 132 mg, (69%). NMR: 3.17 (s, 3H), 3.63 (t, 2H), 4.96 (t, 2H), 5.86 (br s, 1H), 7.04 (d, 1H), 7.28-7.44 (m, 2H), 7.60 (d, 1H), 7.88 (s, 1H), 8.56 (s, 1H), 8.64 (d, 1H), 9.28 (s, 1H), 10.0 (s, 1H); m/z: 330.
Reaction SMILES: [ClH:1].[Br:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1.[NH2:10][C:11]1[C:18]([Br:19])=[CH:17][C:16]([Br:20])=[CH:15][C:12]=1[CH:13]=O.[H][H]>[Ni]>[ClH:1].[NH2:10][C:11]1[C:18]([Br:19])=[CH:17][C:16]([Br:20])=[CH:15][C:12]=1[CH2:13][NH:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([Br:2])[CH2:4][CH2:5]1
Reactant: N[C@H]1CC[C@H](Br)CC1
Reactant: Nc1c(Br)cc(Br)cc1C=O
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Product: Nc1c(Br)cc(Br)cc1CN[C@H]1CC[C@H](Br)CC1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
179 g of trans-1-bromo-4-aminocyclohexane hydrochloride and 279 g of 2-amino-3,5-dibromobenzaldehyde are put into a suitable flask. The temperature rises to 60° C. and the mixture is then cooled to 35° C., after which 250 ml of ethylic alcohol are added. The solution is transferred to a suitable, steel reactor for high-pressure hydrogenizing. 10 g of Nickel-Raney are added, the reactor vessel is closed and hydrogen gas is introduced at 1000 psi. The vessel is agitated at ambient temperature for 15 minutes. The contents of the vessel are poured out and the catalyst is filtered. The ether is evaporated under vacuum. The residue is dissolved in 300 ml of absolute ethylic alcohol followed by the addition of gaseous HCl. THe desired product crystallizes and is recrystallized using absolute ethylic alcohol. 300 g of product are obtained which has a melting point of 240°-245° C.
Reaction SMILES: C(OC(=O)C)C.Cl.[CH2:8]([O:10][C:11](=[O:34])[C@H:12]([NH:26]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15](=O)[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=1)[CH3:9].[H][H]>C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C@H:12]1[CH2:13][CH2:14][C@@H:15]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)[NH:26]1)=[O:34])[CH3:9]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 16 h

Procedure:
3,4,5-Trifluorophenyl magnesium bromide (0.35 M diethylether solution, 55 mL) was dropwise added to a tetrahydrofuran solution (100 mL) of (R)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS Register No. 128811-48-3, 4.1 g) over 20 min at −40° C. This reaction solution was stirred at −40° C. for 5 hr. To this solution, a saturated ammonium chloride aqueous solution and ethyl acetate were added. The reaction solution was heated to room temperature. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane ethyl acetate=1:0 to 1:1) to give 4.8 g of (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoic acid ethyl ester. A 4 N hydrochloric acid ethyl acetate solution (30 mL) was added to an ethyl acetate solution (30 mL) of the obtained (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoic acid ethyl ester. This solution was stirred for 16 hr. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To an ethyl acetate solution (50 mL) of the residue, 10% palladium-carbon (100 mg) was added. The resulting reaction solution was stirred under 1 atm of hydrogen atmosphere for 6 hr. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure to give 2.91 g of the title compound. The physical property values of this compound were as follows: