Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:15][CH2:16][N:17]=3)[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.[CH3:18][C:19]1[S:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=1>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:15][CH2:16][N:17]=3)[C:10]([NH:14][C:25]([C:21]3[S:20][C:19]([CH3:18])=[N:23][C:22]=3[CH3:24])=[O:26])=[N:11][C:12]=2[CH:13]=1
Reactant: COc1ccc2c(c1)N=C(N)N1CCN=C21
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: Br
Product: COc1ccc2c(c1)N=C(NC(=O)c1sc(C)nc1C)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine hydrobromide (Intermediate I, Step 3) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid as white solid (4.26 g, 77%): HPLC MS RT=2.05 min, MH+=356.1;
Reaction SMILES: Cl.[C:2]([CH:6]1[CH2:18][CH2:17][C:9]2([O:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10]2)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:22]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>CO>[C:2]([CH:6]1[CH2:18][CH2:17][C:9]2([O:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:10]2)[CH2:8][CH2:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C1CCC2(CC1)CC(CCN)CO2
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(CCNC1CCCCC1)CO2
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 8-t-butyl-3-aminoethyl-1-oxaspiro(4,5)decane hydrochloride (1.10 g, 4 mmol) in methanol (15 ml) was added sodium methylate (4 ml, 1N in methanol), cyclohexanone (0.41 g, 4.2 mmol) zinc chloride (0.32 g, 2.5 mmol) and sodium cyanoborohydride (0.32 g, 5 mmol). The reaction mixture was stirred at room temperature over night. The solvent was removed in vacuo and the residue was taken up in toluene (50 ml)/sat. aqueous sodium carbonate (50 ml). Drying and evaporation of the organic layer furnished the product as a colurless oil (1.3 g). It was purified by flash chromatography (light petroleum/triethylamine 10:1). Evaporation of the fractions containing the product furnished a colourless oil (1.0 g). 1H-NMR (CDCl3, ppm): 3.93 (t,1H); 3.37(t,1H); 2.58(m,2H); 2.37(m, 1H); 2.27(m, 1H); 1.93-0.90(m,24H); 0.85(s,9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)[CH:5]=[CH:4][N:3]=1.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+]>CC(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([B:8]([OH:12])[OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(B(O)O)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (920 mg, 4.2 mmol) in acetone/water [70 mL (1:1)] was added sodium periodate (2.69 g, 12.6 mmol) and ammonium acetate (810 mg, 10.5 mmol), and allowed to stir at room temperature for 12 hours. The reaction mixture was filtered and concentrated under vacuum to afford desired 2-methyl-4-pyridineboronic acid (575 mg). (Note: This material can be used w/o further purification in Example 13.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1.[OH-].[NH4+]>[Pd].CO.CCOC(C)=O>[NH4+:13].[OH-:2].[CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1
Reactant: COC(=O)C(C)Cc1cccc(C#N)c1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(C)Cc1cccc(CN)c1
Reaction time: 24 h
Yield: 144.7 %

Procedure:
A mixture of 3-(3-cyano-phenyl)-2-methyl-propionic acid methyl ester of Step B (62 mg, 0.30 mmol) and palladium on carbon (10%, 50 mg) in MeOH (10 mL), EtOAc (10 mL), and ammonium hydroxide (5 mL) was hydrogenated at 40 psi for 24 h. The catalyst was removed via filtration through Celite with the aid of MeOH. The solvent was removed in vacuo. Chromatography (1:1 hexanes:EtOAc to CH2Cl2:MeOH:NH4OH, 95:5:0.1) provided the title compound of Step C (45 mg). 1H NMR (400 MHz, CD3OD) δ 7.31-7.14 (m, 4H), 3.94 (s, 2H), 3.59 (s, 3H), 2.96 (m, 1H), 2.72 (m, 2H), 1.12 (d, 3H); MS 208 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH3:16])[C@H:7]([OH:15])[CH2:8]2.C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]([CH3:16])[C:7](=[O:15])[CH2:8]2
Reactant: COc1ccc(OC)c2c1C[C@@H](C)[C@H](O)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(OC)c2c1CC(=O)C(C)C2
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of alcohol 5 (10 g, 45 mmol) and dichloromethane (200 mL) at −30° C. was treated dropwise with oxalyl chloride (4.92 g, 24 mL, 0.275 mol). The reaction was stirred at −30° C. for 30 min, cooled to −60° C., and DMSO (6.4 mL) was added slowly over 15 min. The reaction was stirred for one hour, cooled to −78° C. for 30 min, and then treated dropwise with triethylamine (40 mL). The reaction was warmed to room temperature and stirred for 1 hr, followed by the addition of water and dichloromethane with thorough mixing. The organic layer was separated, dried with MgSO4, filtered and the solvent was evaporated to an oil. Purification of this material using flash chromatography (flash silica, 70/30: hexane/EtOAc) afforded 6 as a white crystalline solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=3)[CH:10]=2)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:32][C:28]1[CH:27]=[C:26]([NH:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=4)[CH:10]=3)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]2)[CH:31]=[CH:30][CH:29]=1
Reactant: COCCn1cc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cn1
Reactant: Clc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](Nc2cccc(Cl)c2)C[C@H](C)N3C(C)=O)cn1
Temperature: 120 °C
Yield: 29 %

Procedure:
1-((2S,4R)-4-Amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 7) (100 mg, 0.304 mmol), 1-bromo-3-chlorobenzene (0.072 ml, 0.609 mmol), Davephos (24 mg, 0.061 mmol), Pd2(dba)3 (27.9 mg, 0.030 mmol) and sodium tert-butoxide (58.5 mg, 0.609 mmol) were combined in 1,4-dioxane (3 ml) and the mixture degassed over a period of 20 min. The mixture was heated at 120° C. for 25 min (microwave). The reaction mixture was partitioned between water (100 ml) and DCM (3×100 ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residual brown oil dissolved in DMSO (2×1 ml) and purified by MDAP (formate ×2). The solvent was evaporated under vacuum, the residue dissolved in DCM and applied to a silica cartridge (10 g). The cartridge was eluted with an ethyl acetate/cyclohexane gradient (0-100% over 10 CV followed by holding at 100% ethyl acetate for 5 CV). The appropriate fractions were combined and evaporated under vacuum to give 1-((2S,4R)-4-((3-chlorophenyl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (39 mg, 0.089 mmol, 29% yield) as a colourless glass. LCMS (formate), Rt 1.05 min, MH+ 438.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, of Step A, and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 8.78 (dd, 2H), 8.27 (d, 2H), 7.87 (m, 2H), 7.59-7.50 (m, 3H), 7.18 (m, 1H), 7.11 (m, 3H), 6.75 (d, 1H), 6.64 (d, 1H), 6.59 (s, 1H), 4.39 (s, 2H), 4.35 (s, 2H), 4.31 (s, 2H), 1.48 (s, 9H); MS 546 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>ClCCl.CN(C=O)C>[CH:28]([N:26]([CH3:27])[C:24]1[C:23]([C:31]([F:33])([F:34])[F:32])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (200 mg, 0.42 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light brown solid (140 mg, 63%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:19]=[CH:18][C:17]([O:1][C@@H:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(OCCC2CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1NCC[C@H]1Oc1ccc(OCCC2CC2)nc1

Procedure:
A mixture of (S)-3-hydroxy-pyrrolidin-2-one (0.79 g), 6-(2-cyclopropyl-ethoxy)-pyridin-3-ol (1.4 g), triphenylphosphine (2.25 g), DCM (30 mL) and THF (20 mL) was added DIAD (1.74 g). After 2 days the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1) to provide the title compound. MS ESI+: m/z=263 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.6 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-p-tolylacetic acid (I40) (1.29 g, 4.86 mmol) in THF (70 ml), are added N,N′-methanediylidenedicyclohexanamine (1.20 g, 5.83 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.79 g, 5.83 mmol), and (R)-quinuclidin-3-ol (0.74 g, 5.83 mmol). The reaction was stirred at RT for 15 hours, and then solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to 7/3) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-p-tolylacetate (1.03 g; 57% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:10](=[O:17])[N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[C:26]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[CH2:27][CH2:28][C:29]#[CH:30].C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C.CCCCCC.C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:21]([O:20][C:19]([NH:18][C@H:9]([C:10](=[O:17])[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:8][C:4]1[CH:3]=[C:2]([C:30]#[C:29][CH2:28][CH2:27][C:26]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:7]=[CH:6][CH:5]=1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: C#CCCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)N1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCC#Cc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
tert-Butyl (S)-(3-(3-iodophenyl)-1-oxo-1-(piperidin-1-yl)propan-2-yl)carbamate (Compound SP418, Boc-Phe(3-I)-pip) (5.00 g, 10.91 mmol), tert-butyl pent-4-ynoate (3.36 g, 21.82 mmol) and triethylamine (4.56 ml, 32.7 mmol) were dissolved in DMF (50.0 ml), CuI (0.104 g, 0.545 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.449 g, 0.545 mmol) were added and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with hexane/ethyl acetate (1/1) and washed with a saturated aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-60:40) to afford the title compound (Compound SP430) (4.84 g, 92%).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[N:25]([CH2:26][CH2:27][O:28][CH2:29][CH3:30])[C:24]4[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=4[N:22]=3)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+].C(O)C.O>C(O)CCC.C(OC(=O)C)C.C(O)(=O)C>[CH2:29]([O:28][CH2:27][CH2:26][N:25]1[C:24]2[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=2[N:22]=[C:21]1[CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]([CH3:5])([CH3:6])[C:3]([OH:35])=[O:2])=[CH:12][CH:11]=2)[CH2:16][CH2:17]1)[CH3:30]
Reactant: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)OC)cc3)CC2)nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCO
Solvent: CCO
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)O)cc3)CC2)nc2ccccc21
Yield: 89.6 %

Procedure:
In a reaction vessel, 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid methylester (2.3 g) prepared in the Example 14, sodium hydroxide (0.6 g) and ethylalcohol (13 mL) were introduced, and the mixture was reacted at 50-55□ for 3 hours. Distilled water (20 mL) was added thereto, and acetic acid was added to control the pH to 7. Ethylacetate (50 mL) was added thereto, and the mixture was stirred to separate a layer. The separated organic layer was condensed under reduced pressure. And, butanol (9 mL) was added thereto, and dissolved by heating. And then, it was cooled to precipitate crystals, and the crystals were filtered under reduced pressure to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid (2.0 g, yield 90%, HPLC purity 99% or more).
Reaction SMILES: C(=O)([O:7][C:8]1[N:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH:17]([CH3:19])[CH3:18])[N:9]=1)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:14]([C:12]1[CH:11]=[C:10]([CH:17]([CH3:19])[CH3:18])[N:9]=[C:8]([OH:7])[N:13]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1cc(C(C)C)nc(OC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)nc(O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Tert-butyl 4,6-diisopropylpyrimidine-2-yl carbonate (42 mg) was dissolved in methylene chloride (4 mL). While the solution was cooled with ice, trifluoroacetic acid (1 mL) was added to the solution. The mixture was then stirred at room temperature (20 to 30° C.) for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to give 8.5 mg (30% yield) of the desired product as a brown amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:10]=1)=[O:5])[CH3:2].[Cl:14]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH:11]2[CH2:12][CH2:13]2)[C:10]=1[Cl:14])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(C2CC2)n[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]nc(C2CC2)c1Cl
Reaction time: 15 h
Yield: 89.4 %

Procedure:
To a solution of 5-cyclopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (202 mg) in N,N-dimethylformamide (4 ml) was added at 0° C. N-chlorosuccinimide (199 mg) and stirring was continued at 22° C. for 15 hours. For the workup, The mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue purified by chromatography on silica using a 8:1-mixture of n-heptane and ethyl acetate as the eluent to give 4-chloro-5-cyclopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (215 mg) as a pale yellow liquid. MS (ISP): m/z=215.2 [M+H]+. b) To a solution of 4-chloro-5-cyclopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (210 mg) in dioxane (4 ml) was added at 22° C. a solution of sodium hydroxide (3.0 M, 0.65 ml), and stirring was continued at 22° C. for 15 hours and at 60° C. for 3 hours. For the workup, the mixture was partitioned between aqueous hydrochloric acid (1.0 M) and ethyl acetate, the organic layer was dried and evaporated to give the title compound (161 mg) as a pale yellow solid. MS (ISP): m/z=184.8 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[Cl:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][CH2:33][CH2:34][CH2:35][C:36]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])=[O:37]
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a magnetically stirred solution of 0.300 g (0.63 mmol) of the product of Example 17 in 6 mL of CH2Cl2 at 0° C. was added 70 μL (0.63 mmol) of 4-chlorobutyryl chloride and 96 mg (0.95 mmol) of triethylamine. The reaction was stirred for 1.5 h and allowed to warm to room temperature. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, washed with aq. NaHCO3, brine, then dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 577.0 (M+1), 578.9 (M+3); Rt=5.05 min.
Reaction SMILES: [ClH:1].C1(CNCC(N(CC2C=CC=CC=2)[C@H](C2C=CC=CC=2)C)=O)C=CC=CC=1.C[C@@H](C1C=CC=CC=1)NCC1C=CC=CC=1.[O:45]=[C:46]([N:56]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH3:58])[CH2:47][NH:48][C:49](=[O:55])[O:50]C(C)(C)C>>[ClH:1].[O:45]=[C:46]([N:56]([CH2:65][C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)[C@H:57]([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[CH3:58])[CH2:47][NH:48][C:49](=[O:50])[OH:55]
Reactant: C[C@@H](c1ccccc1)N(Cc1ccccc1)C(=O)CNC(=O)OC(C)(C)C
Agent: C[C@@H](c1ccccc1)N(Cc1ccccc1)C(=O)CNCc1ccccc1
Agent: C[C@H](NCc1ccccc1)c1ccccc1
Agent: Cl
Product: C[C@@H](c1ccccc1)N(Cc1ccccc1)C(=O)CNC(=O)O

Procedure:
2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)phenylethyl}acetamide hydrochloride: By following the procedure of Example 1(a) but replacing dibenzylamine with α(S)-methyl-N-(phenylmethyl)benzene methanamine, ((S)-N-benzyl-α-methylbenzylamine, Oxford Asymmetry Ltd., Abingdon Oxon, UK), tert-butyl N-{2-oxo-2-{(phenylmethyl){1(S)-phenylethyl}amino}ethyl}carbamate was made. The Boc group was removed following the procedure of Example 1(b) to give N-{2-oxo-2-{(phenylmethyl){1(S)-phenylethyl}amino}ethyl}carbamate hydrochloride, which was subjected to reductive amination with benzaldehyde according the procedure of R. F. Borch, Org. Synth., 1972, 52, 124, to give 2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)-phenylethyl}acetamide hydrochloride.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1.O>C(Cl)Cl>[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([N:9]([CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:11][CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:36])[CH:29]=1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: c1ccc(C(CCNCCC2CCCCC2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(NC(=O)N(CCC2CCCCC2)CCC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
46 mg of (2-cyclohexyl-ethyl)-(3,3-diphenyl-propyl)-amine (0.147 mmol, 1 eq) were diluted in 1 mL of DCM. 30 mg (0.172 mmol, 1.2 eq) of 3-isocyanato-benzoic acid methyl ester were then added to the mixture. The reaction mixture was stirred at room temperature for 90 min before adding water, then the aqueous phase was extracted with DCM. The organic phase was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel (eluant: gradient Hept/EtOAc 5/1). 63 mg of the desired urea were obtained. MS (ES+): 499.5+ (M+H)+. TLC: Rf: 0.57 (eluant: heptane/EtOAc: 1/1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].[O:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: BrCCCCCCCCCCCCOc1ccccc1
Product: COC(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1O
Yield: 75 %

Procedure:
The reaction of 2,5-dihydroxybenzoic acid methyl ester with 12-phenoxydodecyl bromide under condition described in Example 101 gave 2-hydroxy-5-[(12-phenoxydodecyl)oxy]benzoic acid methyl ester (75% yield, mp 61°-64° ).