Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[C:5]([N+:21]([O-])=O)=[C:4]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[C:5]([NH2:21])[C:4]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCCc2nccs2)c1C
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCCc2nccs2)c1C
Yield: 94 %

Procedure:
Under a nitrogen purge, 5% platinum on carbon (0.5 g) and toluene (5 mL) were added to a pressure vessel. A solution of (2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}amine (4.7 g, 11 mmol) in toluene (35 mL) was then added. The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for 24 hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to yield 4.12 g of 5,6-dimethyl-2-phenoxy-N4-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}pyridine-3,4-diamine as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: NCCc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2ccc(C(=O)NCCc3ccncc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.3 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (150 mg, 0.60 mmol) in 30 mL of DCM were added 2-(pyridin-4-yl)ethanamine (110 mg, 0.9 mmol), HATU (274 mg, 0.72 mmol) and DIEA (232 mg, 1.80 mmol) at room temperature. Then the reaction mixture was stirred at room temperature overnight. The solution was washed with sat NaHCO3 (2×20 mL), brine (20 mL), then dried over anhydrous sodium sulfate, concentrated under reduce pressure to give crude N-(2-(pyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (250 mg) and used without further purification. LC-MS: 353 [M+H]+, tR=1.22 min
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:22]=[C:23]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:24]=[CH:25][CH:26]=1>CN(C=O)C>[C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)(=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(NCc2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 25 mL of DMF. To the stirred solvent was added 3-(4-Amino-phenyl)-propanoic acid (0.6 g, 3.635 mmol) followed by K2CO3 (1.507 g, 10.905 mmol) and the mixture stirred at RT for 30 minutes. To the resulting mixture was added (3-bromomethyl-phenyl)-phenyl-methanone (1.0 g, 3.635 mmol) and the stirring continued at RT for further 20 h. After completion of the reaction (reaction monitored by TLC), solvent was removed under reduced pressure, and the resulting crude compound was dissolved in water (15 mL). This aqueous layer was acidified with saturated citric acid solution in water (1.5 g in 3 mL water) to pH 5. The compound was obtained after extracting the residue with diethyl ether (100 mL×3). The combined ether layer was washed with saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude mass thus obtained was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate as eluent. The product was obtained as brown sticky solid (0.3 g, Yield: 22.9%): MS (ESI, 120 eV): m/z=360.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.72 (s, 1H), 7.64-7.68 (t, 4H), 7.57-7.60 (d, 1H), 7.48-7.54 (m, 3H), 6.89-6.91 (d, 2H), 6.46-6.49 (d, 2H), 6.18-6.22 (t, 1H), 4.32-4.34 (d, 2H), 2.61-2.66 (d, 2H), 2.38-2.43 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][N:18]([CH2:27][CH2:28][OH:29])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[OH:15][CH2:16][CH2:17][N:18]([CH2:27][CH2:28][OH:29])[C:19]1[CH:26]=[CH:25][C:22]([C:23]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:21][CH:20]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N(CCO)CCO)cc3)nc2c1
Yield: 41 %

Procedure:
2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-[bis-(2-hydroxy-ethyl)-amino]-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-quinazolin-4(3H)-one (120 mg, 41%) was isolated as a yellow solid. Selected data: MS (m/z): 386.15; MP 249-251° C.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:40]=[C:30]2[N:31]=[CH:32][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:34][N:29]2[N:28]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:40]=[C:30]4[N:31]=[CH:32][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:34][N:29]4[N:28]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCOC(=O)c1cnc2nc(S)nn2c1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: CCOC(=O)c1cnc2nc(SC3=C(O)CC(CCc4ccc(OC)c(Cl)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and ethyl 2-mercapto[1,2,4]triazolo-[1,5-a]pyrimidine-6-carboxylate was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [OH:1][CH:2]([CH2:15][N:16](C)CC#C)[CH2:3][N:4]1[C:12](=O)C2[C:6](=[CH:7]C=CC=2)[C:5]1=O.O.NN.[ClH:24].O1CCOCC1>C(O)C>[ClH:24].[ClH:24].[NH2:16][CH2:15][CH:2]([OH:1])[CH2:3][N:4]([CH3:12])[CH2:5][C:6]#[CH:7]
Reactant: C#CCN(C)CC(O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: C#CCN(C)CC(O)CN
Temperature: 0 °C

Procedure:
The phthalimide (6.6 g, 0.024 mole, prepared according to Step A) dissolved in 50 ml of anhydrous ethanol was treated with hydrazine hydrate (1.21 g, 1.18 ml, 0.024 mole) in one portion. The mixture was refluxed for 1 hour, cooled to 0° C., and filtered. The filtrate was evaporated on rotary evaporator to a volume of approximately 15 ml, acidified with 4N HCl in dioxane (0.06 ml, 0.025 mole), and sonicated. The precipitate was filtered at 0° C. and dried in vacuo to provide the title product as an off-white solid 5.1 g. It was used as such in the next step. MS (DCI, m/z: 143 [M+H]+
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][S:14][C:15]1[NH:19][CH:18]=[N:17][N:16]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:21]>O1CCOCC1>[ClH:21].[CH3:11][CH:10]([CH3:12])[CH2:9][C@H:8]([NH2:7])[CH2:13][S:14][C:15]1[NH:19][CH:18]=[N:17][N:16]=1
Reactant: CC(C)C[C@@H](CSc1nnc[nH]1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)CSc1nnc[nH]1
Yield: 100 %

Procedure:
160 mg of [(S)-3-Methyl-1-(4H-[1,2,4]triazol-3-ylsulfanylmethyl)-butyl]-carbamic acid tert-butyl ester were reacted with 2.6 ml of 4M hydrochloric acid in dioxane at it for 2 h. The reaction was concentrated in vacuo and the resulting crude product was used without further purification. 125 mg (100%) of (S)-3-methyl-1-(4H-[1,2,4]triazol-3-ylsulfanylmethyl)-butylamine-hydrochloride were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:14]([O:16]C)Cl.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[F:8])[CH:14]=[O:16]
Reactant: COC(Cl)Cl
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(F)c(F)c1

Procedure:
57 g (0.5 mol) of ortho-difluorobenzene in 250 ml of methylene chloride is added to 100 g (0.75 mol) of anhydrous aluminum chloride. The mixture is stirred (motor) and cooled in an ice bath while 85.5 g (0.75 mol) of dichloromethyl methylether is added dropwise. Vigorous HCl evolution takes place, and the reaction mixture turns orange-red. After the addition, the mixture is stirred at room temperature for 15 minutes, and the liquid phase is decanted into 500 ml of ice and water. The unreacted residue of aluminum chloride is washed with methylene chloride until colorless, and the washings are added to the water. The mixture is shaken well in a separation funnel until the methylene chloride layer is green. The organic layer is washed with saturated potassium carbonate solution until neutral, then dried (MgSO4) and distilled to give 3,4-difluorobenzaldehyde, B.P. 70-74° C./20 min. The dark residue in the distillation pot solidifies on cooling to give tris-(3,4-difluorophenyl)methane, M.P. 95-96° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].OOS([O-])=O.[K+].[CH:25](=O)[CH:26]([CH3:28])[CH3:27]>CN(C=O)C.O>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:25]1[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2nc(C(C)C)n(CC(OC)OC)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.5 g, 2.0 mmol) from Step C of Example 13 in DMF (15 mL) and H2O (0.5 mL) were added oxone (0.8 g, 1.3 mmol) and iso-butyraldehyde (0.2 mL, 2.2 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-2-isopropyl-1H-benzo[d]imidazole-7-carboxylate (0.5 g, 85%): 1H NMR (500 MHz, DMSO-d6) δ 7.79 (dd, J=8.0, 1.0 Hz, 1H), 7.56 (dd, J=7.5, 1.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 4.61 (d, J=5.0 Hz, 2H), 4.38 (t, J=5.0 Hz, 1H), 3.90 (s, 3H), 3.38-3.33 (m, 1H), 3.19 (s, 6H), 1.32 (d, J=7.0 Hz, 6H); MS (ESI+) m/z 306 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]([O:23][CH2:24][CH3:25])[CH2:21][OH:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl([O-])=[O:27].[Na+].[Br-].[K+].C(O)(=O)C>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]([O:23][CH2:24][CH3:25])[C:21]([OH:27])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: CCOC(CO)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(C(=O)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred solution of ethoxy-alcohol 52 (30 g, 0.085 mol) in dichloromethane (300 ml) was added catalytic TEMPO (0.265 g, 0.0017 mol) and stirred for 10 minutes. To the above solution 100 ml aqueous solution containing mixture of sodium chlorite (23 g, 0.25 mol) and potassium bromide (5 g, 0.0425 mol) was added and stirred for 5 minutes. To this reaction mixture was added aq. acetic acid (5 ml, 20%) and stirring was continued for 12 hour at ambient temperature. The reaction mixture was filtered and the solid was washed with D.M. Water (500 ml) followed by washing with dichloromethane (200 ml). Toluene (400 ml) was added to the solid obtained and the resulting mixture was concentrated azeotropically till the volume of mixture remains to 150 ml and cooled in ice bath. The resulting suspension was filtered. The solid obtained was washed with hexane and dried in vacuum to yield ethoxy-acid 53 (25 g, 80.6%).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C=O)C>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1ccc(C(C)C)cc1)OCC

Procedure:
To a mixture of 4-isopropylaniline (4.05 g, 30.0 mmol) and potassium carbonate (6.21 g, 45 mmol) in DMF (100 mL) at room temperature was added 2-bromo-1,1-diethoxyethane (6.50 g, 33.0 mmol). The mixture was then stirred at 80-90° C. until all of the 4-isopropylaniline was consumed (24 h). The solvent was removed in vacuo and the residue was treated with dichloromethane (150 mL), washed with water and brine, dried over anhydrous MgSO4, and then concentrated. Chromatography (silica gel, hexanes:ethyl acetate, 9:1) of the crude product, furnished the pure intermediate, N-(4-isopropylphenyl)-2,2-diethoxyethylamine, as a colorless oil (5.71 g, 75.8%). 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.18-1.32(m, 12H), 2.75-2.91 (m, 1H), 3.24 (d, 2H), 3.52-3.62 (m, 2H), 3.67-3.79 (m, 2H), 3.87 (s, br, 1H), 4.70 (t, 1H), 6.60 (d, 2H), 7.05 (d, 2H).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[N:13][N:14]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.O>[O:11]1[CH:12]=[N:13][N:14]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=1
Reactant: COC(OC)c1ccc(-c2nnco2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2nnco2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To the product from step B (175 mg, 0.80 mmol) in a 1:1 mixture of tetrahydrofuran/water (2 mL) at room temperature was added p-toluenesulfonic acid (50 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 1 h, and partitioned between dichloromethane and sat. aq. NaHCO3. The organic layer was dried with Na2SO4, and concentrated in vacuo to give 100 mg (72%) of the title product, which was used without further purification. MS 175 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([CH3:32])[CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1.CO.CS(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([CH3:32])[CH:22]=2)(=[O:20])=[O:19])=[C:7]([CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1OCC(=O)O
Reactant: CCCCc1ccc(NCC(C)C)c(C)c1
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CCCCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC(=O)O)c(C)c2)c(C)c1
Reaction time: 2 h

Procedure:
To (4-butyl-2-methylphenyl)(2-methylpropyl)amine (21.94 mg, 0.100 mmol) in pyridine (1 mL) was added {[4-(chlorosulfonyl)-2-methylphenyl]oxy}acetic acid (26.5 mg, 0.100 mmol) and reaction stood for 2 hours at room temperature. The sample was then dissolved in a 1:1 mixture of MeOH and DMSO and purified by MDAP Method A2, to provide the desired product, 11 mg. LCMS (M+1) 448, RT 1.44 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:8]([OH:21])[C:9]([CH3:19])([CH3:20])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(COc1ccc(Cl)cc1)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.7 %

Procedure:
13.1 g (0.031 mol) of 1,4-bis-(4-chlorophenoxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one (Example 2) were dissolved in 100 ml of methanol, and 1.4 g of sodium borohydride were added in portions at 0° to 5° C. The mixture was subsequently stirred at room temperature for 5 hours, acidified with 10 ml of 2 N hydrochloric acid and stirred at room temperature for a further 2 hours. The solvent was then distilled off in vacuo and the residue was taken up in 300 ml of methylene chloride. The mixture was stirred with 200 ml of saturated sodium bicarbonate solution, the organic phase was separated off, washed twice with 300 ml of water each time and dried over sodium sulphate and the solvent was distilled off in vacuo. The colorless residue was taken up in 50 ml of diisopropyl ether and the crystals formed were filtered off. 10.8 g (82.7% of theory) of 1,4-bis-(4-chlorophenoxy)-3,3 -dimethyl-1-(imidazol-1-yl)-butan-2-ol were obtained as a diastereomer mixture of melting point 142°-144° C.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3].[CH3:10][OH:11]>>[CH3:10][O:11][C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3]
Reactant: CO
Reactant: O=C(Cl)N1CCNC1=O
Product: COC(=O)N1CCNC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were introduced into 70 parts by volume of ice-cold methanol and the mixture was stirred for 1 hour at room temperature and subsequently for 1 hour at 40°-50° C. After the excess methanol had been stripped off, the residue was recrystallized from acetone.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCC[CH2:12]1.CCO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:11]([O:9][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:10])[CH3:12]
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
After 2-chloropyrimidin-4-carboxylic acid (0.223 g, 1.4 mmol) was dissolved in DCM (7 mL), dicyclohexylcarbodiimide (0.29 g, 1.4 mmol), DMAP (0.017 g, 0.14 mmol) and EtOH (0.1 mL, 1.4 mmol) were added thereto, and the mixture was stirred at room temperature for 24 hours. After the termination of the reaction, the reactant was filtered and separated by column chromatography to obtain the title compound (0.13 g, 50%).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]2[C:24](OCC2C=CC=CC=2)=O)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[NH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][N:53]=1>CN(C=O)C>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:51][C:52]3[CH:57]=[CH:56][N:55]=[CH:54][N:53]=3)=[O:23])[CH2:19][CH2:18][N:17]2[CH3:24])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccncn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: CN1CC[C@@H](C(=O)Nc2ccncn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80 %

Procedure:
1-Methylimidazole (38.2 μl, 0.479 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (100 mg, 0.240 mmol) in 1.0 ml of DMF. The solution was cooled to 0° C., and then mesyl chloride (24.26 μl, 0.311 mmol) was added dropwise at 0° C. 4-Aminopyrimidine (34.2 mg, 0.359 mmol) dissolved in another 1.0 ml of DMF was then added. The reaction mixture was stirred for 3.5 h at rt. The reaction mixture was concentrated and purified by RP-HPLC to afford (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-methyl-N-4-pyrimidinyl-3-pyrazolidinecarboxamide (95 mg, 0.192 mmol, 80%) as a white foam solid. LC-MS (ES) m/e 495.3 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])(=[O:14])=[O:13])=[N:6][CH:7]=[C:8]([CH3:10])[N:9]=1.[C:23]([OH:35])(=O)[CH2:24][C:25]([CH2:30][C:31]([OH:33])=O)(C(O)=O)O>COCCOC>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:5]1[C:4]([O:33][CH2:31][C:30]2[O:35][CH:23]=[CH:24][CH:25]=2)=[N:9][C:8]([CH3:10])=[CH:7][N:6]=1)(=[O:14])=[O:13]
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2ccco2)n1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.04 g of a 60% dispersion in oil) was added to fi rylalcohol (0.034 g) in 1,2-dimethoxyethane (1 mL). After 5 minutes N-(3-Bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 20 part a) (0.1 g) was added and the mixture heated at 40° C. After 16 h, 5% aqueous citric acid (10 mL) was added and the mixture extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried (MgSO4) and the solvent evaporated. Chromatography on silica gel eluting with dichloromethane gave the title compound as a white solid (0.02 g)