Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]([CH3:21])[CH2:17][C:18](Cl)=[O:19])[CH:13]=[CH:14][CH:15]=1.C([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)CC>O>[CH:31]1([C:28]2[CH:27]=[CH:26][C:25]([C:18](=[O:19])[CH2:17][C@H:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH3:21])=[CH:30][CH:29]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COc1cccc([C@H](C)CC(=O)Cl)c1
Reactant: CCC[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc([C@H](C)CC(=O)c2ccc(C3CCCCC3)cc2)c1
Reaction time: 0.25 h

Procedure:
To a methylene chloride suspension of aluminum chloride, a methylene chloride solution of (R)-3-(3-methoxyphenyl)butyric acid chloride was added dropwise under ice cooling. After stirring at the same temperature for 15 minutes, a methylene chloride solution of trans-4-propylcyclohexylbenzene was added dropwise. After the completion of the reaction, the reaction system was added to iced water and the organic layer was separated by adding methylene chloride. The organic layer was washed twice with water and then washed with saturated brine. The aqueous layer was washed with methylene chloride and, after combining the organic layer, the solvent was concentrated to obtain a crude product of (R)-1-(4-cyclohexylphenyl)-3-(3-methoxyphenyl)-butan-1-one. The resulting crude product was purified by column chromatography and recrystallized from ethanol to obtain (R)-1-(4-cyclohexylphenyl)-3-(3-methoxyphenyl)-butan-1-one (R-isomer of the compound represented by the formula (XI-c)).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1([CH3:21])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1.C([O-])(=O)C.[Na+]>O>[CH3:11][C:12]1([CH3:21])[C:16]2[CH:17]=[C:18]([CH:8]=[O:9])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CC1(C)COc2ccccc21
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)COc2ccc(C=O)cc21
Temperature: 100 °C

Procedure:
Phosphorus oxychloride (30.6 g, 0.2 mole) was added dropwise to a mixture of dimethyl formamide (14.6 g, 0.2 mole) and 2,3-dihydro-3,3-dimethyl benzofuran (14.8 g, 0.1 mole) over half an hour. The temperature rose to 55° C. during addition. The temperature was then raised to 100° C. and maintained for 1 hour prior to addition to a hot solution of sodium acetate (75 g) in water (75 ml). After cooling, the organic layer was separated, dried and distilled yielding 5.6 g unchanged starting material bp 35°-40° C. at 0.1 mm and 5.2 g aldehyde bp 85° C. at 0.1 mm. The product contained a little 2,2-dimethyl isomer from the previous stage.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=3)[CH:13]=[N:12]2)=[C:5]([CH3:28])[CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:35]1[CH2:41][CH2:40][CH2:39][C@H:36]1[CH2:37][OH:38]>CN(C)C(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:14]2[CH:13]=[N:12][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:35]4[CH2:41][CH2:40][CH2:39][C@H:36]4[CH2:37][OH:38])=[CH:4][C:5]=3[CH3:28])=[O:27])[C:16](=[O:17])[CH:15]=2)=[N:21][CH:22]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccc(Cl)cn2)cc1=O
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(CN2CCC[C@H]2CO)ccc1C(=O)Cn1ncc(OCc2ccc(Cl)cn2)cc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 7b, 110 mg, 0.24 mmol) in N,N-dimethylacetamide (2 mL) is added Cs2CO3 (194 mg, 0.60 mmol) and L-prolinol (37 mg, 0.36 mmol). The reaction mixture is stirred for 2 days at room temperature. The mixture is purified via reverse phase HPLC chromatography (Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.[NH2:23][C@H:24]([C:31]([O:33][CH3:34])=[O:32])[CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([NH:23][C@H:24]([C:31]([O:33][CH3:34])=[O:32])[CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:11])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 15 h

Procedure:
To 4.43 g of Z-Ser(But)-OH and 3.18 g of HCl.H-Ser(But)-OMe in 30 ml of dimethylformamide are added at 0° 1.89 ml of N-ethylmorpholine, 2.29 g of HOBt and 3.4 g of dicyclohexylcarbodiimide. After standing for 2 hours at 0° and for 15 hours at 20°, the resulting product is filtered off, the filtrate is concentrated by evaporation and taken up in ethyl acetate. After extraction of the solution with sodium bicarbonate, dilute hydrochloric acid and water, the solution is concentrated by evaporation to leave as oil Z-Ser(But)-Ser(But)-OMe; Rf (toluene/acetone 1:1)=0.70.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([CH3:18])([CH2:15][C:16]#[N:17])[C:11](OC)=[O:12])=[CH:4][CH:3]=1.[H][H]>N.CO.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2([CH3:18])[CH2:15][CH2:16][NH:17][C:11]2=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(CC#N)c1ccc(Cl)nc1OC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1nc(Cl)ccc1C1(C)CCNC1=O
Yield: 90.4 %

Procedure:
A Parr bottle was charged with a solution of methyl 2-(6-chloro-2-methoxypyridin-3-yl)-3-cyano-2-methylpropanoate (2.35 g, 8.73 mmol) in 7 M ammonia in MeOH and a slurry of Raney nickel (5.82 g, 67.9 mmol, washed 2× with water and 4× with MeOH) in 7 M ammonia in MeOH (99 mL total to charge both reagents, 690 mmol). The reaction was shaken with hydrogen (30 psi) for 6 h. The catalyst was filtered through a pad of Celite® under nitrogen rinsing with EtOH. The filtrate was then concentrated to give a light green oil/foam. Purification by silica gel column chromatography (80 g RediSep Gold column, 30-100% Ethyl acetate/Heptanes) provided 3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpyrrolidin-2-one (1.9 g, 90%) as a white solid. 1H NMR (600 MHz, CDCl3) δ: 1.56 (s, 3H), 2.08 (ddd, 1H), 2.58 (dt, 1H), 3.37 (td, 1H), 3.40-3.46 (m, 1H), 3.97 (s, 3H), 5.86 (br. s., 1H), 6.89 (d, 1H), 7.61 (d, 1H); MS (ES+)(M+H) 241.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]1=[O:22].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH2:31][C:30]#[CH:29])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[N:12]([CH3:21])[C:11]1=[O:22]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(O)cc(F)cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(F)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 65 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
4.8 g (15 mmol) of 3-(2,4-difluoro-6-hydroxyphenyl)-1-methyl-6-trifluoromethyluracil and 3.2 g (23 mmol) of potassium carbonate were suspended in 50 ml of N,N-dimethylformamide, and 2.5 g (21 mmol) of propargyl bromide was dropwise added thereto at room temperature. After stirring at from 60 to 70° C. for 5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained crude crystals were washed with isopropyl ether to obtain 5.0 g (yield: 92.63%) of the desired product as yellowish brown powder. Melting point: 159-162° C.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]([CH3:10])[N:4]=1.[OH-:12].[Na+].OO>O>[F:11][CH:2]([F:1])[C:3]1[C:7]([C:8]([OH:12])=[O:9])=[CH:6][N:5]([CH3:10])[N:4]=1
Reactant: [OH-]
Reactant: Cn1cc(C=O)c(C(F)F)n1
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cn1cc(C(=O)O)c(C(F)F)n1
Temperature: 42.5 °C
Yield: 83 %

Procedure:
A 3-neck 250 ml round bottomed flask was fitted with a magnetic stirrer and thermometer. Water (130 g), the product of example 1 (compound of formula IX) (6.50 g) and aqueous sodium hydroxide (8.17 g) were charged to the reactor, and the resulting solution heated to 40-45° C. A 35% hydrogen peroxide solution (39 g) was added over 1 hr, and the mixture then stirred at 40-45° C. for 0.5 hr [83% yield of desired product (compound of formula XI)−quantitative HPLC]. The pH of the reaction mass was adjusted to 2.5 by addition of 36% aqueous hydrochloric acid solution. The resulting precipitate was isolated by filtration and washed with water. Drying (60° C., 10 mbar) gave the desired product (XI) as pale yellow, free-flowing powder [69% yield of desired product−quantitative HPLC].
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].C([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1)(=O)C.[OH-].[Na+].Cl>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:37][C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: CC(=O)Oc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.5 %

Procedure:
To a solution of the product of Example 11 (460 mg) in DMF (10 mL) was added 60% sodium hydride (38 mg) and the reaction stirred at room temperature for 30 minutes before the addition of 4-(chloromethyl)phenyl acetate (280 mg). The reaction mixture was then stirred at room temperature for 17 hrs. Additional 60% sodium hydride (38 mg) was added and the reaction was stirred for a further 2 hours. NaOH (5N, 2 mL) was added and the reaction was stirred at room temperature for 90 minutes. The reaction mixture was acidified with HCl (2N) and extracted into ethyl acetate. The organics were washed with water and brine, dried over magnesium sulphate and evaporated to yield the sub-titled compound (500 mg).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[N:30]([CH2:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43]CC)=[O:42])[CH2:36][CH2:35]3)[CH2:31][CH3:32])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[N:30]([CH2:33][C@H:34]3[CH2:35][CH2:36][C@H:37]([CH2:40][C:41]([OH:43])=[O:42])[CH2:38][CH2:39]3)[CH2:31][CH3:32])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 1.5 h

Procedure:
To a stirred solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl](ethyl)amino]methyl}cyclohexyl)acetate (Step C; 29 mg; 0.042 mmol) in EtOH (2 mL) was added 4 M KOH (400 μL). The reaction was stirred for 90 min, neutralized with aq. citric acid and partitioned between EtOAc (10 mL) and H2O (10 mL). The aqueous layer was re-extracted with EtOAc (10 mL) and the combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by preparatory silica gel chromatography (eluted with 2:1 Hexanes:EtOAc+1% AcOH) to afford (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl](ethyl)amino]methyl}cyclohexyl)acetic acid as a clear glass. LCMS=669.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.91 (s, 1 H), 7.80 (s, 2 H), 7.57 (s, 1 H), 7.52 (d, J=8.3 Hz, 1H), 7.22 (d, J=8.5 Hz, 1 H), 5.77 (d, J=8.0 Hz, 1 H), 4.79 (d, J=16.2 Hz, 1 H), 4.57 (d, J=16.2 Hz, 1H), 4.02-3.99 (m, 1 H), 3.05-2.95 (m, 2 H), 2.93-2.84 (m, 2 H), 2-19 (d, J=6.9 Hz, 2 H), 1.82-1.75 (m, 4H), 1.74-1.68 (m, 1 H), 1.43-1.37 (m, 1 H), 1.01 (t, J=7.0 Hz, 3 H), 0.99-0.88 (m, 4 H), 0.66 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:28])[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3cccnc3)c2C(N)=O)cc1
Yield: 70 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 1.50 g (5.51 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 57 and nicotinic acid instead of cyclopentyl acetic acid to obtain 1.45 g of 1-(4-t-butylbenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 70%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O[C:28]([C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[S:35]([C:38]1[N:42]2[C@:43]([CH3:68])([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]4[CH:63]=[N:64][CH:65]=[N:66][CH:67]=4)=[CH:58][CH:57]=3)[C:44](=[O:54])[N:45]([C:46]3[CH:51]=[C:50]([Cl:52])[CH:49]=[C:48]([Cl:53])[CH:47]=3)[C:41]2=[N:40][CH:39]=1)(=[O:37])=[O:36])=[O:29])(C)(C)C.Cl.C([O:74][C:75](=[O:79])[C@@H:76]([CH3:78])[NH2:77])(C)(C)C.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[Cl:53][C:48]1[CH:47]=[C:46]([N:45]2[C:41]3=[N:40][CH:39]=[C:38]([S:35]([N:31]4[CH2:32][CH2:33][CH2:34][C@H:30]4[C:28]([NH:77][C@H:76]([CH3:78])[C:75]([OH:79])=[O:74])=[O:29])(=[O:36])=[O:37])[N:42]3[C@:43]([CH3:68])([CH2:55][C:56]3[CH:57]=[CH:58][C:59]([C:62]4[CH:63]=[N:64][CH:65]=[N:66][CH:67]=4)=[CH:60][CH:61]=3)[C:44]2=[O:54])[CH:51]=[C:50]([Cl:52])[CH:49]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reaction time: 16 h
Yield: 44 %

Procedure:
TBTU (0.078 g) and (S)-1-[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (Example 14) (0.10 g) were combined in 7% DMF-CH2Cl2 (3.2 mL) at room temperature. D-Alanine-tert-butyl ester hydrochloride (0.044 g), followed by DIPEA (0.07 mL), was then added and the reaction solution was stirred for 16 h. The reaction was diluted with CH2Cl2, poured into 1N HCl, and extracted with CH2Cl2. The organic layers were washed with saturated aqueous NaHCO3 followed by H2O. The combined organic phase was dried (MgSO4), filtered and concentrated. The resultant residue was re-dissolved dissolved in either 50% trifluoroacetic acid—CH2Cl2 or 4N HCl-dioxane (5 mL) and stirred at room temperature for 2 h. Following aqueous workup the residue was purified by silica gel chromatography to afford the title compound (0.045 g) as a foam (698.9, M+1).
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:33][CH2:32]1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:44][C:41]2[CH:40]=[CH:39][C:38]([CH2:37][N:34]3[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]3)=[CH:43][CH:42]=2)=[O:14])=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: CCCP(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 875 μL, ˜1.5 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (306 mg, 1.0 mmol), 4-[(4-methyl-1-piperazinyl)methyl]benzeneamine (Chem. Abstr. Reg. Number: 70261-82-4; 205 mg, 1.0 mmol) and triethylamine (83 μL, 6.0 mmol) in 8 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is crystallised from ethanol-ethyl acetate to give the title compound as a crystalline solid, m.p. 153–155° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].O=[C:8]1[C:14]2C=CC=[CH:18][C:13]=2[N:12]([C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:2]1[C:5]2[CH:14]=[CH:8][CH:9]=[CH:10][C:11]=2[N:12]([C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:22][CH:21]=2)[CH2:13][CH2:18][CH2:3]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Methyltriphenylphosphonium bromide (4.30 g) is suspended in tetrahydrofuran (100 ml) and thereto is added potassium t-butoxide (1.58 g) under ice-cooling. The mixture is stirred at -5° C. for 1 hour and thereto is added 5-oxo-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.60 g) and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice-water (200 ml) and extracted with ethyl acetate. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2), and recrystallized from ethyl acetate/n-hexane to give 5-methylidene-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.34 g) as white powder, m.p. 216°-217° C.
Reaction SMILES: [CH2:1]([N:3]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:4]1([C:7]([O:9]C)=[O:8])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:3]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)(=[O:12])=[O:13])[C:4]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 80.4 %

Procedure:
A solution of 14A (1.3 g, 4.33 mmol) in dioxane (40 mL) was added with 10% NaOH aq. solution (20 mL) and the mixture was heated at 50° C. overnight. The organic solvent was removed under reduced pressure and the aqueous phase was acidified with 10% HCl. The solid formed was collected by filtration, washed with water (2×20 mL) and dried to afford 15A as white solid (1.0 g, 81% yield). 1HNMR (DMSO, 200 MHz) δ 1.10 (t, 3H, J=7.2), 1.65 (bs, 4H), 7.39 (m, 2H), 7.84 (m, 2H), 12.90 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[O:12][S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14].[NH2:20][C:21]1[N:26]=[C:25]([Cl:27])[CH:24]=[C:23]([CH3:28])[N:22]=1>C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[C:23]([CH3:28])[N:22]=[C:21]([NH:20][C:17](=[O:18])[NH:16][S:13]([O:12][C:5]2[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:19])(=[O:15])=[O:14])[N:26]=1
Reactant: COC(=O)c1cccc(OC)c1OS(=O)(=O)N=C=O
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1cccc(OC)c1OS(=O)(=O)NC(=O)Nc1nc(C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 5.4 g (0.02 mol) of the product from Example 1 in 10 ml of methylene chloride is added dropwise to 2.9 g (0.02 mol) of 2-amino-4-chloro-6-methylpyrimidine in 50 ml of methylene chloride at 0° C. The mixture is subsequently stirred at 25° C. for 24 hours and diluted with 50 ml of methylene chloride, and the organic phase is washed twice with 50 ml of 2N hydrochloric acid each time and once with water. After drying with sodium sulfate and removing the solvent on a rotary evaporator, an oily product remains, which crystallizes on trituration with diisopropylether. 7.8 g (91% of theory of methyl 2-[3-(4-chloro-6-methylpyrimidin-2-yl)-ureidosulfonyloxy]-3-methoxybenzoate of melting point 140°-143° C. are obtained.
Reaction SMILES: NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][N:40]([C:45]4([C:49]([O:51][CH3:52])=[O:50])[CH2:48][CH2:47][CH2:46]4)[C:41]3=[O:44])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)([O-])=O>>[NH2:26][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][N:40]([C:45]4([C:49]([O:51][CH3:52])=[O:50])[CH2:46][CH2:47][CH2:48]4)[C:41]3=[O:44])=[CH:37][CH:36]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)CCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCC1
Yield: 71 %

Procedure:
The compound of example 574 was prepared analogous to the compound of example 6 by reduction of the compound of example 573.