Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][C@@H:14]([C:16]([OH:18])=[O:17])[N:13]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40](Br)=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][C@@H:14]([C:16]([OH:18])=[O:17])[N:13]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)c(-n2ccc(C)n2)c1
Temperature: 80 °C

Procedure:
To a solution of (2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid (74 mg, 0.10 mmol, Step 2) in EtOH (4 mL) was added KHCO3 (84 mg, 1.0 mmol). The reaction mixture was degassed, fitted with a 1 atm CO balloon, then treated with PdCl2(PPh3)2 (14 mg, 0.02 mmol). The reaction was degassed once more with 1 atm CO and then heated to 80° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo and the residue was partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/AcOH/EtOH) provided (2S)-8-[2-amino-6-[(1R)-1-[4-ethoxycarbonyl-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([CH3:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].[CH3:27][NH:28][NH2:29]>C1(C)C=CC=CC=1.CCO.CCOCC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:5]2[C:4]3[C:1]([CH3:2])=[N:29][N:28]([CH3:27])[C:8]=3[C:7](=[O:10])[N:6]2[C:11]2[CH:12]=[C:13]([CH3:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[CH:21][CH:22]=1
Reactant: CNN
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
To a stirred solution of 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-1,3-dimethylpyridin-2(1H)-one (Step 57.1) (500 mg, 1.341 mmol) in toluene (5 mL) and EtOH (5 mL) was added methyl hydrazine (0.353 mL, 6.71 mmol) and the reaction mixture was heated up and stirred at 110° C. for 18 hr. The reaction was concentrated under reduced pressure. The resulting mixture was diluted with AcOH (10 ml), heated up and stirred at 100° C. for 1 hr, concentrated under reduced pressure and quenched with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAc. Trituration in Et2O afforded the title product (191 mg, 0.499 mmol, 37% yield) as white solid. tR: 3.83 min (HPLC 1); tR: 0.91 min (LC-MS 2); ESI-MS: 383 [M+H]+ (LC-MS 2); Rf=0.09 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.97 (m, 6H) 3.33 (s, 3H) 3.89 (s, 3H) 6.04 (s, 1H) 7.24 (d, J=8.2 Hz, 2H) 7.30-7.37 (m, 3H) 7.69 (d, J=2.7, Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:5]2[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:8][C:4]=2[C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>CC(C)=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:5]2[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:8][C:4]=2[C:3]=1[S:17]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])(=[O:19])=[O:18]
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Solvent: CC(C)=O
Product: CCN(CC)S(=O)(=O)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Reaction time: 2 h

Procedure:
5,6,7-Trichloro-2-(trifluoromethyl)-4-benzimidazolesulphonyl chloride (22 parts) in dry acetone (80 parts) was added dropwise to a solution of diethylamine (12 parts) in dry acetone (16 parts). The temperature was kept below 30° and the reaction mixture stirred for 2 hours. The solvent was evaporated and the residue treated with 6N hydrochloric acid. The solid product was collected, washed with water and dried (23 parts). Recrystallisation from toluene (charcoal) gave the required product as pale coloured needles (21.6 parts; m.p.[melting point] 152°-154°; 89.7%).
Reaction SMILES: C1N2CCN(CC2)C1.[Cl:9][C:10]1[C:11](Cl)=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17]C)=[O:16].[Cl:21][C:22]1[CH:23]=[C:24]([OH:46])[CH:25]=[CH:26][C:27]=1[CH:28]([CH3:45])[C:29]([OH:44])([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]=[CH:39][CH:38]=[N:37]2)[C:30]([F:33])([F:32])[F:31].[Li+].[OH-]>CN(C=O)C.C(N(CC)CC)C>[Cl:9][C:10]1[C:11]([O:46][C:24]2[CH:25]=[CH:26][C:27]([CH:28]([CH3:45])[C:29]([OH:44])([C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[N:40]=[CH:39][CH:38]=[N:37]4)[C:30]([F:31])([F:32])[F:33])=[C:22]([Cl:21])[CH:23]=2)=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2nccnc2c1)C(F)(F)F
Agent: C1CN2CCN1CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(c1ccc(Oc2ncc(C(=O)O)cc2Cl)cc1Cl)C(O)(c1ccc2nccnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DABCO (2 mg) was added to a mixture of methyl 5,6-dichloronicotinate (27 mg, CAS. Reg. No. 56055-54-0), 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinoxalin-6-yl-propyl)-phenol (50 mg), and triethylamine (17 mg) in DMF (5 ml). The mixture was stirred at room temperature overnight. Aqueous LiOH solution (1N, 1 ml) was added and then stirred for 2 hours to hydrolyze the intermediate ester. The mixture was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (10 mg) as a white foam. MS (m/e)=536.1 [M+H+].
Reaction SMILES: [CH:1]1([C:6]([CH:9]2[CH2:33][C:32]([CH3:35])([CH3:34])[C:12]3[CH:13]=[C:14]4[C:22](=[CH:23][C:11]=3[C:10]2([CH3:37])[CH3:36])[CH2:21][C:20]2[CH:19]=[C:18]3[C:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][C:27]([CH3:29])([CH3:28])[C:17]3=[CH:16][C:15]4=2)([CH3:8])[CH3:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Cl[Si:44]([CH3:47])([CH3:46])[CH3:45]>C1COCC1>[CH3:45][Si:44]([CH3:47])([CH3:46])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]([CH:9]2[CH2:33][C:32]([CH3:35])([CH3:34])[C:12]3[CH:13]=[C:14]4[C:22](=[CH:23][C:11]=3[C:10]2([CH3:37])[CH3:36])[CH2:21][C:20]2[CH:19]=[C:18]3[C:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][C:27]([CH3:29])([CH3:28])[C:17]3=[CH:16][C:15]4=2)([CH3:8])[CH3:7])[CH:2]=1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(C)(C)C1C=CC=C1)C2(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(C)(C)C1C=CC([Si](C)(C)C)=C1)C2(C)C
Yield: 93.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.66 g (1.34 mmol, 1 eq) of 2-(cyclopentadienyl)-2-(1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorenyl)propane was placed at room temperature. Then, 10 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light brown solution). To the solution, 0.88 ml (1.43 mmol, 1.07 eq) of n-BuLi (hexane solution) was dropwise added over a period of 1 to 2 minutes. The ice bath was removed, and the solution was stirred at room temperature for 66 hours (dark violet solution). After the solution was cooled with an ice bath, 0.8 ml (6.31 mmol, 4.71 eq) of chlorotrimethylsilane was dropwise added by a syringe (reddish brown solution). The ice bath was removed, and the solution was stirred at room temperature for 2.5 hours. The resulting light yellow solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quen ching. After the soluble component was extracted with 30 ml of diethyl ether, the organic phase was washed with a saturated saline solution. The organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a slightly yellow amorphous product. The amorphous product was purified by silica gel column chromatography (developing solvent: hexane) to obtain 0.71 g of a white solid (yield: 93%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1.C(O)C(F)(F)F>>[NH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:18][C:12]3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][C:11]=3[O:34][CH3:35])[N:24]=2)=[CH:26]1
Reactant: CN1CCNCC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
A mixture of 1-methylpiperazine (148 mg, 1.48 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 224 mg, 0.59 mmol) and trifluoroethanol (5 mL) was sealed into a microwave tube and heated to 120° C. for 1 h in a microwave reactor and then cooled to r.t. The mixture was then concentrated in vacuo. Trituration of the resulting brown gum with ethanol and then diethyl ether gave a solid that was collected by filtration and dried under vacuum to give the title compound (89 mg, 33%) as a pale brown solid; 1H NMR: 3.02-3.13 (4H, m), 4.00 (3H, s), 6.86 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.31 (1H, d), 7.45 (1H, d), 8.08 (1H, s), 8.33 (2H, dd), 8.82 (1H, d), 11.81 (1H, s); m/z: ES+ MH+ 460.5.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.CC(C)([O-])C.[K+].P(Cl)(OCC)(OCC)=O.[N+:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])#[C-:37]>CN(C)C=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:37]=[N:36][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C1CN=C(c2ccccc2F)c2cc(I)ccc2N1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1F)c1cc(I)ccc1-2
Reaction time: 0.08 h

Procedure:
A stirred solution of 3.8 g (0.01 mol) of 7-iodo-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 50 ml of dimethyl formamide was cooled in an ice bath under an atmosphere of nitrogen. Potassium t-butoxide, 1.29 g (0.0115 mol) was added and after stirring for 5 minutes, 2.59 g (0.015 mol) of diethyl chlorophosphate was added and the stirring was continued for 5 minutes. A mixture of 2.26 g (0.02 mol) of ethyl isocyanoacetate in 50 ml of dimethylformamide that had been treated with 2.24 g (0.02 mol) of potassium t-butoxide just prior to the addition, was then added. After 5 minutes the ice bath was removed and the stirring was continued for 3 hours. The mixture was acidified with 2 ml of glacial acetic acid, diluted with 200 ml of saturated sodium bicarbonate solution and extracted with two 125 ml portions of toluene which were dried and evaporated. The residue was crystallized from ethyl acetate. For analysis, the crude product was chromatographed over silica gel using methylene chloride/ethyl acetate 1:1 (v/v) and then crystallized from ethyl acetate/hexane to give pure product with mp 200°-202°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:23]=[C:22]([S:24][NH2:25])[S:21][N:20]=1.C(=O)(O)[O-].[Na+]>COCCOC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:23]=[C:22]([S:24]([NH2:25])=[O:6])[S:21][N:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NSc1nc(-c2ccccc2Cl)ns1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: NS(=O)c1nc(-c2ccccc2Cl)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A solution of 3.45 g of 85% m-chloroperoxybenzoic acid in 100 ml of DME was added to a solution of 4 g of 3-(2-chlorophenyl)-1,2,4-thiadiazole-5-sulfenamide in 150 ml of DME at -70° C. over an hour. The resulting solution was stirred for 2 hours at -70° and thereafter warmed to room temperature. Concentration gave a solid which was stirred with 100 ml of sodium bicarbonate solution overnight. The solid was collected and the filtrate was extracted with ethyl acetate/dichloromethane. Concentration gave 0.7 g of solid which was recrystallized in benzene to give 0.52 g of solid, m.p. 130°-131°.
Reaction SMILES: C([O:8][CH2:9][CH2:10][S:11][C:12]([F:30])([F:29])[C:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)C1C=CC=CC=1.[H][H].O>C(O)C.[Pd]>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:13]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:12]([F:30])([F:29])[S:11][CH2:10][CH2:9][OH:8]
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a solution of 1-(2-benzyloxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g, 2.2 mmol) in ethanol (20 ml), palladium black (20 mg, catalytic) was added, followed by stirring at room temperature and 1 atmospheric pressure in a hydrogen gas for 12 hours. After the completion of the reaction, an insoluble matter was filtered off. The solvent was then distilled off under reduced pressure. To the residue so obtained, water was added, followed by extraction with chloroform. The chloroform solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure. To the residue, isopropyl ether was added for crystallization, whereby 2-(2,4-difluorphenyl)-1,1-difluoro-1-(2-hydroxyethyl)thio-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.46 g, yield: 55.0%) was obtained as colorless crystals.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])=[O:6])(=O)C>ClCCl>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:10]([CH:11]4[CH2:12][CH2:8][O:9][CH2:10][CH2:11]4)=[O:13])=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)OCOC(=O)C1CCOCC1
Yield: 80 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (579.0 mg, 1.69 mmol) in dichloromethane (14 mL) and tetrahydro-pyran4-carbonoylmethy carbonochloridate (71) gave the titled product in 80% yield (716.5 mg, 1.36 mmol). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H), 7.24 (t, 1H), 7.16 (dd, 1H), 5.72 (q, 2H), 5.38 (t, 1H), 4.76-4.84 (m, 1H), 4.06 (t, 1H), 3.93 (dq, 2H), 3.78 (dd, 1H), 3.68 (ddd, 1H), 3.55 (dt, 1H), 3.55 (dt, 2H), 3.14-3.19 (m, 4H), 3.10 (dt, 1H), 2.57 (tt, 1H), 2.34-2.47 (m, 2H), 2.17-2.22 (m, 2H), 1.69-1.86 (m, 4H). MS-APCI (m/z+): 529 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[C:3]=1[C:4]([N:6]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C2CCCCO2)[CH:9]=1)=[O:5].Cl.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[C:3]=1[C:4]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:26]=1)=[O:5]
Reactant: O=C(c1c(Cl)cc(Cl)cc1Cl)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)N(Cc1cccc(O)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
To a solution of crude 2,4,6-trichloro-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-benzamide (0.076 g, 0.13 mmol) prepared in Step A in 0.5 mL methanol was added HCl (0.78 mL of a 4.0M solution in 1,4-dioxane, 3.12 mmol) and triethylsilane (0.20 mL, 1.30 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. The residue was purified by preparative TLC (1.0 mm silica gel layer, eluting with 10% methanol/methylene chloride) to afford 0.022 g of 2,4,6-trichloro-N-(3-hydroxy-benzyl)-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide. 1H NMR (CDCl3) δ 7.13 (s, 2H), 7.10–7.05 (m, 1H), 7.03 (d, 2H, J=12.0 Hz), 6.79–6.67 (m, 3H), 6.58 (d, 2H, J=11.6 Hz), 4.94 (s, 2H), 4.17–4.13 (m, 2H), 3.15 (bs, 2H), 2.99 (bs, 4H), 1.94 (bs, 4H).
Reaction SMILES: CCO.C([Cl:7])(=O)C.[CH3:8][C:9]([C:12]1[O:16][C:15]([CH2:17][S:18][C:19]2[S:23][C:22]([NH:24][C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])=[N:21][CH:20]=2)=[N:14][CH:13]=1)([CH3:11])[CH3:10]>O>[ClH:7].[CH3:11][C:9]([C:12]1[O:16][C:15]([CH2:17][S:18][C:19]2[S:23][C:22]([NH:24][C:25]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[O:26])=[N:21][CH:20]=2)=[N:14][CH:13]=1)([CH3:8])[CH3:10]
Reactant: CC(=O)Cl
Agent: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCNCC3)s2)o1
Solvent: CCO
Solvent: O
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 40 mL of absolute EtOH cooled in an ice-bath was added acetyl chloride (0.28 mL, 3.9 mmol) dropwise. The reaction mixture was allowed to warm to room temperature over 30 min then N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]-thio]-2-thiazolyl]-4-piperidinecarboxamide (1.50 g, 3.94 mmol, 1 eq) was introduced in one portion with stirring to give a thick slurry. Water (˜4 mL) was added until homogeneous then concentrated in vacuo to give a crude pale yellow solid. The crude material was recrystallized (aq EtOH) to afford the title compound (70%) as a white solid, mp 256-258°. Analysis calc'd for C17H24N4O2S2.HCl: C, 48.96; H, 6.04; N, 13.43; S, 15.38; Cl, 8.50. Found: C, 48.69; H, 5.99; N, 13.24; S, 15.27; Cl, 8.31.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[NH:16][C:15](=[O:17])[CH:14]=[C:13]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:12]=1.[CH3:24][C:25](C)=O>[OH-].[Na+].ICC>[CH2:24]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[NH:16][C:15](=[O:17])[CH:14]=[C:13]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:12]=1)[CH3:25]
Reactant: O=c1cc(N2CCOCC2)nc(Cc2nc3ccccc3[nH]2)[nH]1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCI
Product: CCn1c(Cc2nc(N3CCOCC3)cc(=O)[nH]2)nc2ccccc21

Procedure:
The product can be prepared as in stage 1 of Example 11, but using 155 mg of 2-(1H-benzimidazol-2-ylmethyl)-6-(morpholin-4-yl)pyrimidin-4(3H)-one in 15 ml of acetone, 0.375 ml of sodium hydroxide (2N) and 0.6 ml of iodoethane. After purification by silica column chromatography, eluent: CH2Cl2/MeOH: 95/05, 30 mg of 2-[(1-ethyl-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([O:3]C(C)(C)C)=O.Cl.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[C:35]([N+:41]([O-:43])=[O:42])=[CH:34][C:30]=1C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1.CN(C1C=CN=CC=1)C.O>[Cl:28][C:29]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[C:35]([N+:41]([O-:43])=[O:42])=[CH:34][C:30]=1[C:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A mixture of benzyl N-Bocglycinate (3 g, 11.3 mmol) and HCl in dioxane (20 mL) was stirred at rt for 2 h. Solvents were evaporated under reduced pressure and was diluted with dioxane (20 mL) and triethylamine (2.24 mL, 16.24 mmol). Then 2-chloro-4,5-dinitrobenzoic acid (2 g, 8.1 mmol) was added and cooled to 5° C. A solution of DCC (5.8 g, 28.1 mmol) in dioxane (20 mL) was added followed by catalytic amount of DMAP. The reaction mixture was stirred at rt for 5 h. Few drops of water was added to the reaction mixture and again stirred for 15 min. Reaction mixture was cooled to 0° C. and filtered. The solid was washed with ether (50 mL) and EtOAc (50 mL). The filtrate was poured into water and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layer was washed with brine and dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:acetone (90:10) as eluents to give the product as a pale yellow color solid (2.5 g, 75%), mp 122-124° C. 1H NMR (400 MHz, CDCl3): δ 8.30 (1H, s), 7.96 (1H, s), 7.39 (5H, s), 6.94 (1H, br s), 5.25 (2H, s), 4.32 (2H, d, J=4.8 Hz); LC-MS (negative ion mode): m/z 392 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[OH:18][C:19]1[CH:24]=[C:23]([OH:25])[N:22]=[C:21]([SH:26])[N:20]=1.N1CCCCC1.O>C(O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:15][C:12]([CH:13]=[C:24]2[C:23](=[O:25])[NH:22][C:21](=[S:26])[NH:20][C:19]2=[O:18])=[CH:11][CH:10]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=S)NC(=O)C1=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Temperature: 80 °C
Yield: 55.7 %

Procedure:
A suspension of 0.242 g (1 mmol) of 5-(2-trifluoromethylphenyl)furfural, 0.144 g (1 mmol) of 4,6-dihydroxy-2-mercaptopyrimidine, and a drop of piperidine in 6 ml of ethanol was stirred with heating at 80° C. for 4 hours. Upon cooling, the orange suspension was poured into 50 ml of water and sonicated for 10 minutes. Filtration of the orange solvent and drying provided 0.204 g of the product as an orange powder.