Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H:2](C(O)=O)CC(O)=O.C(OC(Cl)=O)C1C=CC=CC=1.C(OC(N[C@H](C(O)=O)CC(O)=O)=O)C1C=CC=CC=1.[NH2:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CO>[CH3:2][O:50][C:49](=[O:51])[C@H:41]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH2:40]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
A process for producing an addition compound of a dipeptide ester and an amino acid ester comprising reacting aspartic acid and benzyloxycarbonyl chloride in an aqueous solution in the presence of a base to prepare a solution containing N-benzyloxycarbonylaspartic acid, reacting separatedly phenylalanine with methanol in the presence of an acid to produce phenylalanine methyl ester adding a base therein to liberate the phenylalanine methyl ester, adding to admix an organic solvent capable of forming binary phases with water to extract the phenylalanine methyl ester in the organic solvent phase, separating the phases, adding an acidic aqueous solution into the organic solvent phase to admix and contact with to back-extract the phenylalanine methyl ester into the aqueous phase, separated the phases, admixing the aqueous phase with the above prepared aqueous solution containing N-benzyloxycarbonyl-aspartic acid, adding a proteolytic enzyme into the resulting mixture liquor under conditions under which no substantial deactivation of the enzyme occurrs, reacting N-benzyloxycarbonylaspartic acid with phenylalanine methyl ester to deposit an addition compound of N-benzyloxycarbonyl-α-L-aspartly-L-phenylalanine methyl ester and phenylalanine methyl ester and recovering the addition compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][C:14](OC)=[O:15].[Li+].[BH4-].[NH4+].[Cl-].CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CCO)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 72.2 %

Procedure:
Methyl 2-(2-chloro-5-methoxy-4-nitrophenyl)acetate (10.2 g, 41.86 mmol) was dissolved in dry THF (200 mL) and cooled to 0° C. A 2M solution of LiBH4 in THF (41.86 mL, 83.73 mmol) was added at 0° C. over 20 minutes then the mixture was allowed to warm to room temperature and stirred for 5 hours. Saturated NH4Cl solution was added to the reaction cautiously and stirred further for 15 minutes then EtOAc (150 mL) and water (150 mL) were added. The separated aqueous phase was extracted with EtOAc (100 mL) then the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 0-2% methanol in DCM to give the title compound (7.0 g, 72%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Br[CH2:26][CH2:27][CH3:28]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:26][CH2:27][CH3:28]
Reactant: CCCBr
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Product: CCCN(c1c(C)cc(C)cc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Yield: 88.3 %

Procedure:
In the same manner as described in Example 9, 0.699 g (2.0 mmol) of the product of Example 62 and 0.295 g (2.4 mmol) of 1-bromopropane provided 0.691 g (88%) of the desired product as a yellow gum after preparative TLC eluting with 1:3 EtOAc:hexane. Electrospray Mass Spec 392.2(M+H).
Reaction SMILES: [N:1]12[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2.[Ba].C(N)CN(CCN)CCN.C(C=O)=O>>[N:1]12[CH2:18][CH2:17][N:16]=[CH:15][CH:14]=[N:13][CH2:12][CH2:11][N:10]([CH2:9][CH2:8][N:7]=[CH:6][CH:5]=[N:4][CH2:3][CH2:2]1)[CH2:19][CH2:20][N:21]=[CH:22][CH:23]=[N:24][CH2:25][CH2:26]2
Reactant: C1CNCCN2CCNCCNCCN(CCN1)CCNCCNCC2
Agent: NCCN(CCN)CCN
Agent: O=CC=O
Agent: [Ba]
Product: C1=NCCN2CCN=CC=NCCN(CCN=C1)CCN=CC=NCC2

Procedure:
There is interest in nitrogen-donor cryptands for the preparation of room-temperature stable alkalides and electrides (Kim, J., et al., J. Am. Chem. Soc., 121 10666-10667 (1999)) which led to reinvestigation of the synthesis of 1,4,7,10,13,16,21,24-octaazabicyclo[8.8.8]hexacosane (1), the aza analog of cryptand [2.2.2] (Xie, Q., et al., J. Am. Chem. Soc. 122 6971-6978 (2000)). Compound 1 was used for the preparation of the first barium sodide (Redko, M. Y., et al., JACS 125 2259-2263 (2003)). A reaction sequence in which tren is condensed with glyoxal to form the intermediate 1,4,7,10,13,16,21,24-octaazabicyclo [8.8.8]hexacosa-4,6,13,15,21,23-hexaene (2) has been described by Smith et al (Smith, P. H., et al., J. Org. Chem. 58 7939-7941 (1993)), who also obtained the crystal structures of both compounds 1 and 2. While this method is satisfactory, it leads to gelatinous byproducts which lowered the yield and required the separation of compound 2 from the gelatinous byproducts via a 3-day Soxhlet extraction followed by filtration. The gels are polymers formed from the reactants and are very difficult to separate from the compound 2. The purified compound 2 was then reduced with LiAlH4 in THF or NaBH4 in MeOH to give a low overall purified yield of 45% of compound 1. A large excess of moderately expensive reducing agent(s) is required.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.B(OB([O-])[O-])([O-])[O-].CC([O-])=O.[K+].CCOC(C)=O.CCCCCC>CS(C)=O.[Pd]>[NH:6]1[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 22 h
Yield: 21.3 %

Procedure:
To a mixture of 4-bromoindole (1, 9.80 g, 50 mmol), pinacole diborate (2, 13.97 g, 55 mmol), and KOAc (14.72 g, 150 mmol) in DMSO (200 mL) was added Palladium catalyst PdCl2(dppf) CH2Cl2 (1.22 g, 1.5 mmol). The system was degassed, and then charged with nitrogen for three times. The mixture was stirred at 80° C. oil bath under nitrogen for 22 hours. TLC2 showed the complete disappearance of the starting material 4-bromoindole (1). The mixture was cooled to room temperature, and then poured to water (1 L). The product was extracted with ethyl acetate for three times. The combined extracts were washed by brine for five times to remove DMSO solvent, and then dried over Na2SO4. During the washing step, the catalyst may precipitate out, which was removed by filtration. The ethyl acetate solution was filtered and condensed. The residue was purified on a silica gel column eluting with EtOAc-hexane (9:1). The first fraction provided the side product indole (1.25 g, 21% yield), Rf 0.55 (EtOAc-Hexane 5:1). The second fraction provided the product 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole as a white solid (3, 8.01 g, 66%), Rf 0.46 (EtOAc-Hexane 5:1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.CO>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: FC(F)c1cc(Br)ccn1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: NC1=NC(c2cccc(Br)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Reaction time: 0.42 h
Yield: 18.8 %

Procedure:
n-Butyllithium (0.254 mL, 0.63 mmol) was dropwise added to 4-bromo-2-(difluoromethyl)pyridine (120 mg, 0.58 mmol) in anhydrous THF (5.00 mL) at −78° C. under argon atmosphere. The reaction mixture was stirred for 25 min. N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (235 mg, 0.58 mmol) in anhydrous THF (5.00 mL) was dropwise added. The reaction mixture was stirred for 2 h, then methanol (5 mL) was added and the temperature was allowed to reach room temperature. The reaction mixture was partitioned between aqueous ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (47.1 mg, 18%).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.[N:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39][CH:38]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:43][C:40]4[CH:41]=[CH:42][N:37]=[CH:38][N:39]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: Nc1ccncn1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccncn3)ccc21
Temperature: 0 °C
Yield: 100 %

Procedure:
A flask was charged with perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.256 g, 0.419 mmol) and pyrimidin-4-amine (0.048 g, 0.503 mmol). A septum was attached and THF (2.096 ml) was added under N2 flow. The mixture was cooled to 0° C. A THF solution of lithium bis(trimethylsilyl)amide (0.880 ml, 0.880 mmol, 1 M) was added dropwise to give a brown solution with a tan precipitate. The solution was maintained at 0° C. for 20 min, and allowed to warm to rt and maintained for 2 h. The reaction mixture was partitioned between 1 N HCl (10 mL) and EtOAc (20 mL), the layers were separated and the aqueous layer was extracted with 1:1 MeOH:EtOAc (1×20 mL). The combined organic layers which were dried (Na2SO4) and concentrated to provide 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide (0.219 g, 0.419 mmol), which was of sufficient purity for the subsequent step. m/z (ESI) 521.1 (M+H)+.
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([OH:56])=[C:30]([C:32]2(O)[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:33]2=[O:54])[CH:31]=1>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([OH:56])=[C:30]([CH:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH:41]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:33]2=[O:54])[CH:31]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(Br)ccc1O
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: O=C1C(c2cc(Br)ccc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one, the title compound was obtained (99%) as a white powder: 1H NMR (300 MHz, CDCl3) δ 7.39-7.20 (m, 11H), 7.11-7.06 (m, 4H), 6.82 (d, 1H), 6.57-6.51 (m, 1H), 5.04 (s, 1H); MS (ES+) m/z 471.2 (M+1), 473.2 (M+1).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH3:16])[C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6]1.CN(C)C=O.I[CH2:23][CH:24]1[CH2:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25]1.[ClH:33]>C(N(CC)CC)C>[ClH:33].[O:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[CH2:28][CH:24]1[CH2:23][N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH3:16])[C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6]1
Reactant: ICC1Cc2ccccc2O1
Reactant: CCC(=O)N(C)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCC(=O)N(C)C1CCN(CC2Cc3ccccc3O2)CC1
Yield: 30 %

Procedure:
5.1 g of N-piperid-4-yl-N-methylpropionamide acetate, 90 ml of dimethylformamide and 6.3 ml of triethylamine are introduced into a 250 ml three-necked flask. 6.6 g of 2,3-dihydro-2-iodomethylbenzofuran are poured onto the mixture which is heated to 60°-65° C. This temperature is maintained for 15 hours. The reaction mixture is evaporated to dryness and the residue is taken up in ethyl acetate and extracted with 150 ml of N hydrochloric acid. The aqueous phase is rendered alkaline with sodium hydroxide in the presence of ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. The solvent is evaporated to yield a base in the form of a brown oil, which is converted into a salt with 3.8N ethereal hydrogen chloride to yield the desired compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC(C)(C)COc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC(C)(C)C)ncn1
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
In 1.6 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.2 ml of a solution containing 0.06 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.2 ml of a solution containing 0.16 g of 4-chloro-6-(2,2-dimethylpropyloxy)pyrimidine in tetrahydrofuran at room temperature, followed by stirring for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 4-(2-butynyloxy)-6-(2,2-dimethylpropyloxy)pyrimidine (the present compound (6)).
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@@H:19]([OH:23])[CH:20]([CH3:22])[CH3:21])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:45]1(C)[CH:50]=CC(S(O)(=O)=O)=C[CH:46]=1.C(=O)(O)[O-].[Na+]>COC(OC)(C)C>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]1[C@H:19]([CH:20]([CH3:21])[CH3:22])[O:23][C:45]([CH3:50])([CH3:46])[O:24]1)=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Product: CC(C)[C@@H]1OC(C)(C)O[C@@H]1[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C

Procedure:
50 mg of (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylpentyl]imidazole-4-propionamide and 50 mg of p-toluenesulphonic acid in 3 ml of dimethoxypropane are stirred at room temperature overnight. The reaction mixture is thereafter poured into 2N sodium bicarbonate solution and extracted with ethyl acetate. The organic phases are washed with water, dried and evaporated, whereby there is obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(S)-(cyclohexylmethyl)[(4R,5S)-5-isopropyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]imidazole-4-propionamide as a solid, MS: 673 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH:19]3[CH2:21][CH2:20]3)[C:9]2=[O:22])[CH:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C(C)=CC=CC=1>[CH:19]1([C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:10]2[CH2:11][CH2:12][N:8]([C:4]3[CH:3]=[C:2]([CH:23]4[CH2:25][CH2:24]4)[N:7]=[CH:6][N:5]=3)[C:9]2=[O:22])[CH2:21][CH2:20]1
Reactant: O=C1N(c2cc(Cl)ncn2)CCN1c1cnccc1C1CC1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C1N(c2cc(C3CC3)ncn2)CCN1c1cnccc1C1CC1
Yield: 38.9 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(6-chloropyrimidin-4-yl)-3-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-38a: 140 mg, 0.44 mmol) was reacted with cyclopropyl boronic acid (46 mg, 0.533 mmol), Pd(PPh3)4 (26 mg, 0.02 mmol), potassium carbonate (123 mg, 0.888 mmol) and xylene (10 mL) in seal tube at 125° C. for 14 hours. Purification by column chromatography on silica gel (1% methanol in chloroform) afforded 55 mg of the product (38.73% yield).
Reaction SMILES: COC1C=CC([CH:9]2[C:14]3[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[O:17][C:13]=3[CH:12]=[CH:11][N:10]2[CH3:22])=CC=1.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:17][C:16]1[CH:18]=[CH:19][C:20]([C@@:13]23[O:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[C@@H:14]2[CH2:9][N:10]([CH3:22])[CH2:11][CH2:12]3)=[CH:21][CH:15]=1
Reactant: COc1ccc(C2c3c(oc4ccccc34)C=CN2C)cc1
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CC[C@]2(c3ccc(O)cc3)Oc3ccccc3[C@@H]2C1
Yield: 84.2 %

Procedure:
A mixture of 3.46 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(4-methoxyphenyl-2-methyl-benzofuro[3,2-c]pyridine and 3.57 g of lithium thiomethoxide in 30 ml of dry hexamethylphosphoramide was heated under a drying tube at 140° for 41/2 hours. The reaction mixture was diluted with 350 ml of water, and the pH was adjusted to 7 by slow addition of 2N HCl with stirring. As the pH reached neutral, the product precipitated out. The mixture was cooled to 0° and stirred for 30 minutes. The precipitated material was filtered, washed with water and then with a small amount of ether, and dried to give 2.77 g (84.2%) of crystalline solid, m.p. s 209°, 215°-217°. Recrystallization from ethanol afforded 2.33 g (70.8%) of crystals, m.p. s 215°, 222°-224°.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:11][CH2:12][C:13](Cl)=[O:14].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:13]1(=[O:14])[C:7]2[C:6](=[CH:5][C:4]3[CH2:3][CH2:2][CH2:1][C:9]=3[CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)CCC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc3c(cc21)CCC3
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The mixture of 11.8 g indane (0.1 mol) and 10 ml 3-chloropropionyl chloride (0.12 mol) was added to suspension of 16 g AlCl3 (0.55 mol) in 100 ml CH2Cl2 at 0° C. After then reaction mixture was poured into ice and HCl, the organic layer was isolated; the aqueous one was extracted with CH2Cl2 (2*50 ml). The combined organic phase was washed by NaHCO3, dried over MgSO4 and evaporated. The residue was added carefully to conc. H2SO4 (100 ml), warmed to 70° C. and stirred after then 30 min at the same temperature. The mixture was cooled and poured into ice. Precipitate was filtered, washed by water and dried, to give 12.4 g of product (72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][C:21]([NH2:23])=[O:22]>>[C:21]([CH2:20][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])(=[O:22])[NH2:23]
Reactant: NC(=O)CI
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(OCC(N)=O)c([N+](=O)[O-])c1

Procedure:
Reaction of 1.41 g of 4-methoxy-2-nitrophenol, 3.04 g potassium carbonate and 3.61 g of iodoacetamide analogously to the process described in Example 55) gives 2-carbamoylmethoxy-5-methoxynitrobenzene: mp 190°-1° C.; Rf (O)=0.58; FAB-MS: (M+H)+ =227; anal. calc. for C9H10N2O5 : C47.79%, H4.46%, N12.38%; found C47.90%, H4.48%, N12.58%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with 1-methylpiperazine (0.84 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2) gradually changing to dichloromethane:methanol (95:5) to afford the title compound (312 mg).
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][CH:9]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:33][CH:34]=1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: CCCCCCCOc1ccccc1C=CC(CCCCC(=O)O)Cc1ccc(C(=O)O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccccc1CCC(CCCCC(=O)O)Cc1ccc(C(=O)O)cc1
Reaction time: 2 h

Procedure:
31.6 mg (0.07 mmol) of 6-(4-carboxybenzyl)-8-(2-heptoxyphenyl)-7-octenoic acid from Ex. 25 and 20 mg of palladium/activated carbon (10%) are added to 5 ml of ethyl acetate and, at room temperature and under atmospheric pressure, hydrogenated with hydrogen. After two hours, the mixture is filtered through Celite and concentrated under reduced pressure.