Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH:28]([CH3:52])[CH:29]([OH:51])[CH2:30][O:31]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH2:11]([O:27][CH:28]([CH3:52])[CH:29]([O:51][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:30][OH:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(C)C(CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5.01 g of 50% sodium hydride in 100 ml of dimethylformamide containing 15.79 g of benzyl bromide at 0° C., was added 46 g of 3-(hexadecyloxy)-1-(triphenylmethoxy)-2-butanol in 50 ml of dimethylformamide. This mixture was stirred overnight at room temperature then poured into water and extracted with petroleum ether. The organic extract was dried and the solvent removed. The residue was dissolved in a mixture of 190 ml of methanol and 100 ml of tetrahydrofuran, then 400 mg of p-toluenesulfonic acid was added. This mixture was allowed to stand overnight, then the solvent was removed. The residue was dissolved in petroleum ether, washed wtih saturated aqueous sodium bicarbonate, dried and the solvent removed, giving and oil. This oil was purified by HPLC using the system hexane:ethyl acetate (9:1), giving 21.84 g of the desired compound as an oil.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:20])[N:6]3[N:21]=[CH:22][N:23]=[C:5]3[C:4]=2[CH:3]=1.CN1C([Sn](CCCC)(CCCC)CCCC)=[CH:28][C:27](C(F)(F)F)=N1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]3[S:10][C:2]([CH:27]=[CH2:28])=[CH:3][C:4]=3[C:5]3=[N:23][CH:22]=[N:21][N:6]3[C:7]2=[O:20])=[CH:13][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)nn1C
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)sc32)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc2c(s1)n(Cc1ccc(OC)cc1)c(=O)n1ncnc21
Temperature: 100 °C

Procedure:
To a mixture of 8-bromo-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (80 mg, 0.20 mmol) in toluene (2 ml) was added 1-methyl-5-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazole (135 mg, 0.31 mmol). The resulting mixture was heated to 100° C. for 16 hours and cooled to room temperature. It was filtered through a pad of celite with DCM washing. The resulting filtrate was concentrated under reduced pressure, diluted in methanol, filtered and purified directly via reverse-phase HPLC to afford the title compound.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:13]2[C:10]3[CH:11]=[CH:12][C:7]4[N:8]([C:4]([CH3:3])=[N:5][N:6]=4)[C:9]=3[CH:15]=[C:14]2[CH3:16])=[CH:21][CH:20]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(C)cc3c2ccc2nnc(C)n23)cc1
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
Sodium hydride (0.032 g, 0.81 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.268 mmol, Example 2, Step 5) in DMF (4 mL). After 10 minutes, p-methoxybenzyl chloride (0.036 mL, 0.27 mmol, Aldrich) was added. The reaction was stirred for 45 minutes, then was quenched with water, diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a white solid (49 mg, 60%).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])([OH:3])=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCOCC1>[N:14]1([C:1]([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=Cc1cccc(OCC(=O)O)c1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=Cc1cccc(OCC(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(Carboxymethoxy)benzaldehyde (1.63 g, 9.05 mmol) was dissolved in p-dioxane (20 ml) and cooled in an ice bath and then N,N'-carbonyldiimidazole (1.9 g) was added in one portion. The reaction mixture was stirred for 30 minutes, then morpholine (0.8 ml) was added and the mixture was warmed to room temperature and stirred until the reaction was complete. The solvent was removed in vacuo, the residue was partitioned between CHCl3 (100 ml) and 2N HCl (75 ml), the layers were separated, and the aqueous layer was extracted with CHCl3 (2×75 ml). The organic layers were combined, dried over MgSO4 and stripped to afford an oil which was combined with the product from a similar experimental run and purified by column chromatography on silica gel eluting with chloroform to afford 2.1 g of 3-[4-morpholinylcarbonylmethoxy]benzaldehyde.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[IH:13].[OH-].[Na+]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([I:13])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: I
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc2c(I)ccnc2c1
Temperature: 130 °C

Procedure:
4,7-Dichloroquinoline (50 g) was added, in small portions, to HI (425 mL) at r.t. and then heated at 130° C. for 5 h. The mixture was cooled, poured into ice/H2O (600 mL), made basic (pH 10) with 10N NaOH, and extracted with CHCl3. The combined organics were washed with NH4OAc buffer, 10% Na2S2O3 and brine. Drying (Na2SO4) and concentration provided the title compound that was used as such.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C@H:13]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[C@H:13]([C:22]([OH:24])=[O:23])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A solution of (2S,5R)-tert-Butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (1.50 g, 3.73 mmol) in methylene chloride (5.0 mL) was ice-cooled, and trifluoroacetic acid (5.0 mL) was added, and reacted at the same temperature for 30 min. and then at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, then water and 6.5% sodium bicarbonate aqueous solution was added to the residue. After pH was adjusted to ca. pH 8, aqueous layer was washed with ethyl acetate. To this aqueous layer was added 5% potassium hydrogen sulfate aqueous solution. After pH was adjusted to ca. pH 5.6, the aqueous layer was extracted with ethyl acetate. After the organic layer was washed with saturated brine, dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to afford 0.913 g of the title compound (yield 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:10][S:9][C:8]=2[CH:21]=1)([O-])=O.O.NN>CO.[Ni]>[N:16]1([CH2:15][CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][S:9][C:8]3[CH:21]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)SCCN2CCCN1CCCC1
Yield: 90.7 %

Procedure:
A solution of 7-nitro-4-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.55 g, 1.789 mmol) in dry methanol (10 mL) was treated with hydrazine hydrate (0.652 mL, 17.89 mmol) followed by Raney-Nickel (0.1 g, 1.789 mmol) at room temperature. The resulting mixture was stirred at reflux for 5 minutes using a pre-heated oil bath. The reaction was then brought to room temperature, filtered through a pad of Celite, and washed with methanol (3×10 mL). The combined methanol layers were evaporated, and the crude material was purified by flash column chromatography (5:95 (2 M NH3 in MeOH):CH2Cl2) to obtain the title product (0.45 g, 91%) as a syrup. 1H NMR (DMSO-d6) δ 6.51 (d, 1H, J=9.3 Hz), 6.26-6.23 (m, 2H), 4.41 (s, 2H), 3.37-3.30 (m, 2H, merged with water peak), 3.11 (t, 2H, J=6.9 Hz), 2.98-2.95 (m, 2H), 2.42-2.37 (m, 6H), 1.67-1.60 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:29])[C:23]=2[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH2:22][CH2:21][N:20]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Oc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(O)cccc32)nc(N2CCOCC2)cc1=O
Yield: 23 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 270 mg of indolin-4-ol and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 85 mg of 2-[2-(4-hydroxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C#Cc2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-4-ethynylbenzene (2.76 g, 20.20 mmol) in THF (50 mL) at −78° C. was added 2.5 M butyllitium (8.81 ml, 22.03 mmol in hexane) and stirred for 1 h at −78° C. tert-Butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (Compound 1.2, 5 g, 18.36 mmol) was added. The mixture was stirred at −78° C. for 30 min, then warmed up to 0° C., stirred for another hour at the same temperature, and diluted with water. The organic layer was separated and the aqueous was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, and the drying agent was filtered off. The filtrate was concentrated. The residue was purified by silica gel column chromatography using gradient elution (5 to 30%, EtOAc/hexane). LC-MS m/z 292.06 [M−56+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:29][C:11]3([C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:12]3=O)[CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O.C[OH:31]>[Pd]>[NH2:1][C:4]1[C:9](=[O:31])[NH:8][C:7]2[CH2:10][C:11]3([CH2:29][C:6]=2[CH:5]=1)[C:19]1[C:14](=[N:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:12]3
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc([N+](=O)[O-])cnc3C2)c2cccnc21
Reactant: CO
Agent: [Pd]
Product: C[Si](C)(C)CCOCN1CC2(Cc3cc(N)c(=O)[nH]c3C2)c2cccnc21
Reaction time: 4.5 h

Procedure:
A mixture of 10% Pd/C (20 mg) and (±)-3-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (117 mg, 0.284 mmol) was stirred vigorously in MeOH (5 mL) under an atmosphere of hydrogen (ca. 1 atm). After 4.5 h, the mixture was filtered through a pad of Celite, washing extensively with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=383 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55](Cl)(=[O:59])[CH:56]([CH3:58])[CH3:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:55](=[O:59])[CH:56]([CH3:58])[CH3:57])[CH2:49][CH2:48]1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isobutyryl chloride as starting materials in 32% yield. LCMS for C28H33ClN7O2 (M+H)+: m/z=534.2.
Reaction SMILES: [ClH:1].Br[C:3]1C=C(NC)C(N)=C[CH:8]=1.[Na].[N:13]1([C:19]2[N:20]=[C:21](CC(O)=O)[NH:22][C:23](=O)[CH:24]=2)[CH2:18]COC[CH2:14]1>CN(C=O)C.N1C=CC=CC=1>[ClH:1].[CH3:18][N:13]([CH3:14])[CH2:19][CH2:24][CH2:23][N:22]=[C:21]=[N:20][CH2:3][CH3:8]
Reactant: O=C(O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CNc1cc(Br)ccc1N
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN=C=NCCCN(C)C

Procedure:
In a round-bottom flask, the 4-bromo-N2-methylbenzene-1,2-diamine hydrochloride prepared above (1.2 g) is placed in a mixture of DMF (10 ml) and pyridine (10 ml) with magnetic stirring, and then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (968 mg) and then the sodium salt of (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid, obtained in stage 2 of Example 1 (1.2 g) are added. The mixture thus obtained is stirred at ambient temperature (20° C.) overnight. After evaporation of the reaction medium, glacial acetic acid (20 ml) is added and the resulting mixture is brought to reflux (90 min). The reaction medium is concentrated, and taken up in dichloromethane and water at pH 8 (2N sodium hydroxide), so as to form a solid which is filtered off and washed with dichloromethane. The solid obtained is dissolved in methanol, adsorbed onto silica (7 g) and purified by chromatography. Purification is carried out on a silica column (50 g), elution being carried out with a mixture of dichloromethane and 9/1 dichloromethane/MeOH (with CV=75 ml; gradient: 4 CV DCM; 4 CV of 0 to 16% 9/1 DCM/MeOH; 8 CV of 16 to 20% 9/1 DCM/MeOH; 1 CV of 20 to 30% 9/1 DCM/MeOH). The fractions containing the expected compound are combined and evaporated under reduced pressure. 900 mg of 2-[(6-bromo-1-methyl-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are isolated, the characteristics of which are the following:
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CF)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: FC[C@@H]1CCNC1

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.304 g, 1.87 mmol), tert-butyl (3R)-3-(fluoromethyl)pyrrolidine-1-carboxylate (See Intermediate 56) (0.325 g, 1.87 mmol) and ethanol (2 mL) to give the title compound as a white solid (0.421 g): MS (m/e): 104 (M+1).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+:6].[Na+].[Na+].[Cl-].[Na+].[CH2:11](O)C1C=CC=CC=1.[CH3:19][C@@H:20]([C@@H:26]1[C@@:30]2([CH3:46])[C@@H:31]([OH:45])[CH2:32][C@@H:33]3[C@@:38]4([CH3:44])[CH2:39][CH2:40][C@@H:41]([OH:43])[CH2:42][C@H:37]4[CH2:36][CH2:35][C@H:34]3[C@@H:29]2[CH2:28][CH2:27]1)[CH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[CH3:19][C@@H:20]([C@@H:26]1[C@@:30]2([CH3:46])[C@@H:31]([OH:45])[CH2:32][C@@H:33]3[C@@:38]4([CH3:44])[CH2:39][CH2:40][C@@H:41]([OH:43])[CH2:42][C@H:37]4[CH2:36][CH2:35][C@@:34]3([CH3:11])[C@@H:29]2[CH2:28][CH2:27]1)[CH2:21][CH2:22][C:23]([O-:25])=[O:24].[Na+:6]
Reactant: OCc1ccccc1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Product: C[C@H](CCC(=O)[O-])[C@H]1CC[C@H]2[C@]3(C)CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
A composition of sodium deoxycholate (0.5% and 1%) was prepared comprising sodium phosphate (10 mM), sodium chloride (75-90 mM), benzyl alcohol (0.9%), deoxycholic acid, pH 8.3.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)c(OC)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 2-(3,4-Dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.4 g, 2.3 mmol), Na2CO3 (2 M, 2.45 mL), and Pd(PPh3)2Cl2 (9.7 mg, 0.084 mmol) in toluene/ethanol (1:1, 8.0 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-(3,4-Dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 65% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:30][CH2:31][OH:32])[CH2:5][CH2:6][CH2:7][N:8]([CH2:27][CH2:28][CH3:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH2:33](Br)CC.C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O>>[OH:1][CH2:2][CH2:3][N:4]([CH2:30][CH2:31][OH:32])[CH2:5][CH2:6][CH2:7][N:8]([CH2:27][CH2:28][CH2:29][CH3:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCBr
Reactant: CCCCCCCCCCCCCCCCCCN(CCC)CCCN(CCO)CCO
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: CCCCCCCCCCCCCCCCCCN(CCCC)CCCN(CCO)CCO

Procedure:
In like manner, N,N-bis(2-hydroxyethyl)-N'-(n-propyl)-N'-octadecyl-1,3-propanediamine is prepared from n-propylbromide. Its picrate salt melts at 105°-106° C.
Reaction SMILES: [CH2:1]([S:8]([CH2:10][C@@H:11]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([S:8]([CH2:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)Cc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(Cc1ccccc1)C[C@@H]1CCNC1

Procedure:
Using a similar method to that described in Example 93, step 2, (3R)-3-(benzylsulfinyl)methyl-1-(tert-butoxycarbonyl)pyrrolidine (0.2376 g, 0.735 mmol) was reacted with trifluoroacetic acid (1 ml) in dichloromethane (3 ml) to give, after work up, 0.1543 g (94%) of the title compound as a white solid, which was used without further purification. δH (250 MHz, CDCl3) 1.47 (1H, m), 2.09 (1H, m), 2.52-2.72 (4H, m), 2.94 (2H, m), 3.19 (1H, m), 3.96 (1H, d, J=12.9 Hz), 4.06 (1H, dd, J=12.9 and 3.6 Hz), 7.27-7.43 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:26])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:26])[C:15]([C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)=[CH:32][N:33]([CH3:35])[CH3:34])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1ccc(CCNC(=O)Cc2ccc3c(c2)CCCC3)cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 107.7 %

Procedure:
2.65 g (7.50 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, 3.92 g (22.5 mmol) of t-butoxybis (dimethylamino)methane and 30 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 3.30 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide.