Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15]C(=O)C)=[CH:8][CH:7]=1)=[O:5])[CH3:3].BrBr.[OH-:21].[Na+]>C(O)(=O)C.C(O)C>[OH:21][C:2]([C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)=[O:5])([CH3:3])[CH3:1]
Reactant: CC(=O)OCCOc1ccc(C(=O)C(C)C)cc1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(O)C(=O)c1ccc(OCCO)cc1
Temperature: 25 °C

Procedure:
336 g (3.2 mol) of isobutyryl chloride are added dropwise over the course of 40 minutes while stirring to 880 g. (8.8 mol) of anhydrous aluminium chloride in 480 ml of dichloromethane at -5 to 0° C. 540 g. (3.0 mol) of 2-phenoxyethyl acetate are then added dropwise over the course of 2 hours at the same temperature. The reaction mixture is stirred for a further 2 hours at the stated temperature and then poured into a mixture of 1.8 l of concentrated hydrochloric acid and 5 kg of ice. The organic phase is separated off and the aqueous layer is extracted with dichloromethane. The combined organic phases are washed with water, dried and evaporated, and the residue is distilled in vacuo. 740 g. of 4-(2-acetoxyethoxy)phenyl-2-propyl ketone of boiling point 145-152° C./0.3-0.5 torr are obtained. b) 205 g. (1.0 mol) of 4-(2-acetoxyethoxy)phenyl 2-propyl ketone are dissolved in 200 ml of glacial acetic acid, and 192 g. (1.2 mol) of bromine are added over the course of 2 hours with stirring at 25° C. The mixture is then stirred for about a further 10 hours and then poured into 3 L of ice water. The product is extracted with ethyl acetate. The combined extracts are dried, and 365 g. of a viscous oil are obtained by evaporation. This oil is dissolved in 1 L of ethanol, and 380 g. of 32% strength sodium hydroxide solution are added over the course of 20 minutes with stirring at 25° C. The mixture is stirred for a further 10 minutes and the ethanol is then removed. The oily residue is transferred into 3 l of ice water, and this mixture is extracted repeatedly with a total of 1.5 l of ethyl acetate. After drying, filtering and evaporating the solution, 250 g. of an oily crude product are isolated. Through recrystallization from acetone/petroleum ether and/or chromatographic purification, 145 g of 4-(2-hydroxyethoxy)phenyl 2-hydroxy-2-propyl ketone are obtained in the form of a colourless solid of melting point 88°-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[C:27]2[NH:29][CH:30]=[CH:31][C:26]2=[C:25]([N+]([O-])=O)[CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[N:28]=[C:27]2[NH:29][CH:30]=[CH:31][C:26]2=[C:25]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[F:9])[CH:24]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=[N+]([O-])c1cc(Cl)nc2[nH]ccc12
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2cc(Cl)nc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2-fluorophenol (0.77 g, 6.07 mmol) is dissolved in DMF. Potassium tert-butoxide (0.68 g, 6.07 mmol) is added, and the mixture is stirred at room temperature for 30 minutes. Powdered potassium carbonate (0.35 g, 2.53 mmol) and 1 g (5.06 mmol) of 6-chloro-4-nitro-1H-pyrrolo[2,3-b]pyridine (from example XXX) are then added successively. The mixture is stirred at 120° C. for 12 hours. After cooling, the mixture is diluted with ethyl acetate (200 ml). The suspension is filtered off with suction through Celite®, and the filtercake is washed with ethyl acetate. The solution is extracted successively with aqueous sodium bicarbonate solution and sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified by column chromatography (silica gel 60, mobile phase: DCM:acetone=5:1). This gives 0.95 g (67% of theory) of product.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([O:7]CC)=O.[NH:18]([C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:23]=[CH:22][N:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:43]>C(O)C.O1CCOCC1>[ClH:43].[Br:16][C:14]1[CH:15]=[C:10]([C:4]2[C:5](=[O:7])[N:18]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[N:23]=[CH:22][N:21]=3)[NH:2][CH:3]=2)[CH:11]=[N:12][CH:13]=1
Reactant: NNc1cc(N2CCCCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 100° C., 500 mg (1.7 mmol) of the compound from Example 11A, 323 mg (1.7 mmol) of the compound from Example 8A and 58 mg (0.3 mmol) of p-toluenesulfonic acid are stirred in 2 ml of ethanol for 16 h. After cooling to RT, 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added, and the mixture is stirred at RT for 30 min. The precipitate is filtered off, washed first with ethanol and then with diethyl ether and dried under reduced pressure.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([C:28]1[S:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1)[CH2:26][CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:33]([C:30]3[S:29][C:28]([CH2:25][CH2:26][CH3:27])=[N:32][CH:31]=3)=[O:34])=[CH:22][CH:23]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCc1ncc(C(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3cnc(CCC)s3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.7 g of 2-propyl-thiazole-5-carboxylic acid (prepared as described by Clemence et al., Eur. J. Med. Chem. Chimica Therapeutica 1976-11, no. 6, p. 567–570) and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11](Cl)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Product: O=c1c2[nH]c(N3CCCC3)nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
The title compound was prepared from 1,3-di-cyclopropylmethyl-8-chloro xanthine (0.3 g, 0.0011 mol) and pyrrolidine (0.2 g, 0.0028 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C.
Reaction SMILES: C([Li])CCC.Cl[C:7]1[CH:8]=[N:9][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[N:11][CH:12]=1.C1C[O:31][CH2:30]C1>CN(C=O)C>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C:16]2[O:15][N:14]=[C:13]([C:10]3[N:9]=[CH:8][C:7]([CH:30]=[O:31])=[CH:12][N:11]=3)[N:17]=2)=[CH:19][CH:20]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ncc(Cl)cn3)no2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(-c2nc(-c3ncc(C=O)cn3)no2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
n-Butyllithium (4.77 mL, 7.16 mmol) was added to a solution of 5-chloro-2-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrimidine (1.5 g, 4.77 mmol) and THF (50 mL) at −78° C. and stirred for 7 hours DMF (3 mL) was added to the reaction mixture, warmed to 0° C. and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (25 mL) and the organic layer was separated and washed with water (3×25 mL) and brine (1×25 mL) and concentrated in vacuo to provide the title compound (1.13 g, 76% yield) as an orange solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][C@H:8]1[C@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9]1=O)([CH3:4])[CH3:3].Cl.[O:25]([NH2:27])[CH3:26]>N1C=CC=CC=1>[CH3:26][O:25][N:27]=[C:9]1[CH2:10][C@@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[C@H:8]1[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:4])[CH3:1])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 75.6 %

Procedure:
A solution of 12.317 g (34.9 mmol) of [2R,3R]-2,3-Bis(((1,1-dimethylethyl)dimethylsilyl)oxymethyl)cyclobutanone, from Step E, in 20 mL of pyridine was added to a solution of 3.160 g (37.8 mmol) of methoxylamine hydrochloride in 80 mL of pyridine. After stirring the reaction mixture for 70 min at ambient temperature, it was concentrated to approximately 1/4 of the original volume then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on a 5×38 cm silica gel column eluted with 1 L of hexane and 5% acetone in hexane to give 10.228 g (75.7% yield) of the title compound as a mixture of geometrical isomers. .MS DCI-NH3M/Z: 388 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[N:4][CH:3]=1.[CH2:13]([Li])CCC.IC.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: Clc1cncc(NCC2CC2)n1
Reactant: [Li]CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CC1CC1)c1cncc(Cl)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 6-chloro-N-(cyclopropylmethyl)pyrazin-2-amine (0.60 g) in tetrahydrofuran (5 mL) was added dropwise n-butyllithium (3.06 mL, 1.6 M hexane solution) at −78° C. The mixture was stirred at −78° C. for 5 min, and iodomethane (1.02 mL) was added dropwise thereto. The mixture was stirred at −78° C. for 30 min, and further stirred at 0° C. for 1 hr. Saturated aqueous sodium thiosulfate solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→15% ethyl acetate/hexane) to give the title compound (0.46 g, 70%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1B(O)O>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[CH:3][C:4]=2[F:18])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1F
Product: COc1ccc(C)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of example 4 step (i) and (2-methoxy-5-methylphenyl)boronic acid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:23][CH2:24]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-ylmethyl-9H-purine (230 mg, 0.50 mmol), isobutyryl chloride (59 mg, 0.55 mmol) and NEt3 (140 μL, 1.00 mmol) in DCM (10 mL) was allowed to stir at r.t. for 5 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-5%) then further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 40-98%) affording 851 as a white solid (57 mg, 21%). LCMS (method I): RT 3.69 min, [M+H]+ 531.4. 1H NMR (DMSO, 400 MHz): δ 8.01-8.00 (1 H, m), 7.63-7.62 (1 H, m), 7.27-7.23 (2 H, m), 4.40 (1 H, d, J=13.34 Hz), 4.25 (4 H, brd s), 3.94 (1 H, d, J=13.78 Hz), 3.77-3.74 (7 H, m), 3.26 (2 H, q, J=7.45 Hz), 3.01 (1 H, t, J=13.02 Hz), 2.87-2.85 (3 H, m), 2.50-2.50 (1 H, m), 2.12-2.08 (1 H, m), 1.77-1.73 (2 H, m), 1.33 (3 H, t, J=7.44 Hz), 1.29-1.07 (2 H, m), 1.00-0.98 (6 H, m)
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]1([CH3:15])[CH:11]=[CH:10][C:9]([C:12](Cl)=[O:13])=[CH:8][CH:7]=1.[Si]([C:20]#[N:21])(C)(C)C>C(Cl)Cl>[C:6]1([CH3:15])[CH:11]=[CH:10][C:9]([C:12]([C:20]#[N:21])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)C#N)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A 1 M solution of tin chloride in CH2Cl2 (1.3 mL, 1.3 mmol) was added dropwise to an ice water cooled solution of p-toluoyl chloride (10.00 g, 65 mmol) and TMSCN (9.00 mL, 68 mmol). The reaction was monitored to completion over 4 hours by disappearance of the IR acid chloride carbonyl stretch, then quenched by addition of ice water (20 mL) and extracted with CH2Cl2. The organic solution was dried (MgSO4) and concentrated to afford 8.80 g of p-toluoyl cyanide as an orange solid.
Reaction SMILES: Cl.Cl.Cl.Br[C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[N:14]=3)[S:10][C:9]=2[CH:31]=1.[Br:32]C1C2SC=CC=2C=CC=1>>[Br:32][C:31]1[C:9]2[S:10][C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[N:14]=3)=[CH:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc2ccsc12
Reactant: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(Br)cc2s1
Agent: Cl
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2cccc(Br)c2s1

Procedure:
Using the method of [4-(6-bromobenzo[b]thiophen-2-yl)-5-methylpyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 7-bromobenzo[b]thiophene and isolated as a solid. ES+(m/z) 460 (79Br) and 462 (81Br) [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:21])[C:17](Br)([CH3:19])[CH3:18])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[C:11]([O:15][C:16](=[O:21])[C:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:19])[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 140 °C
Yield: 54.4 %

Procedure:
To a solution of 5-chlorosalicylaldehyde (5 g, 32 mmol) in N,N-dimethylformamide (100 mL) was added 2-bromo-2-methyl-propionic acid tert-butyl ester (10.7 g, 48 mmol), Cs2CO3 (3.1 g, 95 mmol). The reaction mixture was heated at 140° C. for 18 h. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over Na2SO4 and concentrated to give 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid tert-butyl ester as a pale yellow solid (Yield 5.2 g, 54%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[CH3:11][C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: CC1(O)CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(O)CCCN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, 3-methylpiperidin-3-ol and triethyl amine in DMF yielding 3-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ol. LCMS (m/z): 238.1 (MH+); LC Rt=1.39 min.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[N:30]=1>CN(C)C=O>[Cl:28][C:29]1[N:30]=[C:31]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: ClCc1cccc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(Cl)n3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloro-6-chloromethyl-pyridine (36.3 mg, 0.22 mmol) described in Manufacturing Example 52-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (39.5 mg, 90%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][N:23]=4)[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH:30]([OH:33])[CH2:31][CH3:32])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:33][CH:30]([C:12]1[C:13]2[N:14]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][N:23]=4)[C:15]3=[N:16][C:17]=2[C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:31][CH3:32])(=[O:3])[CH3:2]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 74.7 %

Procedure:
Acetic anhydride (0.20 mL, 2.10 mmol) was added to a stirred solution of 1-[9-chloro-1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (94.1 mg, 0.229 mmol) in pyridine (1.5 mL) at room temperature, and the mixture was stirred at room temperature for 13 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (77.6 mg, 0.171 mmol, 75%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7](I)[CH:6]=1)=[O:4].[CH2:20]([S:22]([C:25]1[CH:26]=[C:27](C2C3C4N=CC=NC=4NC=3C=CC=2)[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH3:21]>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([S:22]([CH2:20][CH3:21])(=[O:23])=[O:24])[CH:26]=2)[CH:6]=1)=[O:4]
Reactant: CCS(=O)(=O)c1cccc(-c2cccc3[nH]c4nccnc4c23)c1
Reactant: COC(=O)c1cc(I)c2c(c1)[nH]c1ncc(C)cc12
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from Compound 131 according to the procedure outlined in the preparation of Compound 81. MS (ES) [m+H] calc'd for C22H20N2O4S, 409; found 409.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][C:6]([NH:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])=[O:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>CN(C)C=O.O1CCCC1>[CH2:1]([S:3]([CH2:5][C:6]([NH:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])(=[O:40])=[O:4])[CH3:2]
Reactant: CCS(=O)CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.4 g of 1-[4-(N-ethylsulfinylacetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 46) are dissolved in 50 ml of dimethylformamide, and a solution of 3-chloroperbenzoic acid (85%) in 30 ml of tetrahydrofuran is added dropwise at RT. The clear solution is stirred overnight at RT. The mixture is concentrated by evaporation, the residue is dissolved in water and the solution is rendered neutral, extracted with dichloromethane, chromatographed over silica gel and crystallised from ether/petroleum ether/alcohol, yielding 1-[4-(N-ethylsulfonylacetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 135°-136°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH2:7]([NH:19][C:20](N1C=CN=C1)=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CO>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:20]([NH:19][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:21]
Reactant: CCCCCCCCCCCCNC(=O)n1ccnc1
Reactant: NCC(O)CO
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)NCC(O)CO

Procedure:
The preparation was carried out, according to the same process described in Example 1, from 2.3 g of 3-amino-1,2-propanediol of corresponding formula R2—NH—R3, where R2 denoted H and R3 denoted —CH2—CHOH—CH2OH, and 7 g of 1-N-(dodecylaminocarbonyl)imidazole of corresponding formula (II), where R1 denoted C12H25, in 100 cm3 of methanol.