Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:4]=[C:3]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:2]=1.[CH:33](=O)[CH:34]([CH3:36])[CH3:35].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:4]=[C:3]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:2][CH:1]([CH3:27])[CH3:6])[CH:2]=1
Reactant: NCCCNCCCNCc1cc(CNCCCNCCCN)cc(-c2ccccc2)c1
Reactant: CC(C)C=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CNCCCNCCCNCc1cc(CNCCCNCCCNCC(C)C)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round-bottom flask was added the crude N1,N1′-([1,1′-biphenyl]-3,5-diylbis(methylene))bis(N3-(3-aminopropyl)propane-1,3-diamine) (3.5 g, 8.0 mmol) and MeOH (50 mL). To the solution was added isobutyraldehyde (1.15 g, 15.9 mmol) and the reaction mixture was stirred at rt for 24 h. Sodium borohydride (1.2 g, 31.9 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aq. NaOH (10%, 200 mL) and EtOAc (200 mL) were added, and the mixture was stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (200 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as a clear oil which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5](F)[N:4]=1)[CH3:2].O.[NH2:24][NH2:25].C([O-])(O)=O.[Na+]>CC(O)C>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5]([NH:24][NH2:25])[N:4]=1)[CH3:2]
Reactant: CCc1nc(F)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCc1nc(NN)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
2-Ethyl-6-fluoro-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 0.51 mmol) was suspended in 2-propanol (1.0 mL) in a screw-cap reaction vessel. Hydrazine hydrate (0.12 mL, 2.5 mmol) was added, the reaction vessel was sealed and the mixture was stirred at 90° C. for 18 h. Sat. NaHCO3 (aq) (20 mL) was added and the mixture was extracted wth EtOAc (4×35 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 2-ethyl-6-hydrazinyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 96%) as a light yellow solid that was used in the next step without further purification. MS (ESI) m/z: 311.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Al].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>O.C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cl
Agent: [Al]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(O)c(C2=CCCCC2)c1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
15.0 g (0.10 mol) of 4-tert-butylphenol and 7.2 g (0.035 mol) of aluminium isopropylate are added to 100 ml of xylene under nitrogen. To remove the resulting isopropanol, 30 ml of solvent are distilled off. The reaction mixture is heated to 100° C. and charged with 9.8 g (0.10 mol) of cyclohexanone and is then refluxed for 20 hours. The reaction mixture is cooled and charged with 40 ml of water and 10 ml of concentrated hydrochloric acid. The organic phase is separated, washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system hexane/ethyl acetate=19:1 and the pure fractions are crystallised from methanol, giving 6.3 g (27%) of 4-tert-butyl-2-cyclohexen-1-yl-phenol, m.p. 90-93° C. (compound (109), Table 1).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15](Cl)=[O:16])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]2.N1C=CC=CC=1>C(Cl)Cl>[OH:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:19][NH:18][C:15]([C:10]1[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=1[CH2:12][CH2:13][CH3:14])=[O:16])[CH:29]=[CH:28]2
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccccc1
Reactant: NCc1ccc2cc(O)ccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1c(C(=O)NCc2ccc3cc(O)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
A solution of 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride (2.0 g, 8 mmol) in 20 mL of methylene chloride was added dropwise under nitrogen to a mixture of 6-aminomethyl-naphthalen-2-ol (1.63 g, 9.42 mmol), prepared in step 1 of Example 8, and 75 mL of anhydrous pyridine. The reaction stirred at room temperature for 17 h (overnight). The reaction was diluted with methylene chloride and extracted with 1N HCl. The aqueous layer was separated and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give a brown solid. The solid was recrystallized from ethyl acetate and then again from isopropanol. The crystals were collected by filtration and dried under reduced pressure to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (0.767 g, 25%) as a tan solid, mp 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:34])[C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:31](O)=[O:32])=[O:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH2:35][C@@H:36]([CH2:45][CH2:46][CH3:47])[C@H:37]([OH:44])[C:38]([NH:40][CH:41]1[CH2:43][CH2:42]1)=[O:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:34])[C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:20])[CH2:15][C@H:14]3[C:31]([NH:35][C@@H:36]([CH2:45][CH2:46][CH3:47])[C:37](=[O:44])[C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])=[O:32])=[O:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=687.17 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH2:14])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Br[CH2:16][C:17]([C:19]1[N:20]=[CH:21][S:22][CH:23]=1)=[O:18]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:16][CH:17]([OH:18])[C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(CBr)c1cscn1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cscn2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carbomethoxyphenyl)-1-methylethylamine with 4-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel plate using ethyl acetate/methanol =8:2 as eluant.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN1CCNCC1
Product: CN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 30 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 30% yield; NMR Spectrum: 2.10 (s, 3H), 2.27 (br s, 4H), 2.50 (hidden under DMSO, 4H), 2.78 (t, 2H), 4.41 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.42 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 495 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].Br.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Br.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Reactant: CN(C)CCBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCn1c(SCCN(C)C)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), beta-dimethylaminoethyl bromide hydrobromide (0.076 g, 0.325 mmol), potassium hydroxide (0.041 g, 0.739 mmol) in Ethanol (1.738 ml) was refluxed ON. To the cooled solution, water (1 ml) was added and the mixture was extracted with EtOAc 2×. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12, 7.37-7.22, 5.95, 4.71, 3.48, 3.05, 2.76, 2.64-2.58, 2.36, 1.74-1.72, 1.59-1.53, 1.42-1.39; MS (EI) m/z 410 (M+1)
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[S:8][C:9]=1[CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:33]CC1>>[CH3:10][C:9]1[S:8][C:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[N:6][C:5]=1[CH:4]([OH:33])[CH3:3]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1nc(-c2ccc(-c3ccccc3)nc2)sc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1sc(-c2ccc(-c3ccccc3)nc2)nc1C(C)O
Temperature: 25 °C

Procedure:
A solution of [5-methyl-2-(6-phenyl-pyridin-3-yl)-thiazol-4-yl]-acetic acid methyl ester (6.0 g, 18.5 mmol) in THF (500 mL) was added dropwise to a suspension of LAH (0.90 g, 22.2 mmol) in THF (300 mL) at −78° C. After the addition was completed, the reaction mixture was allowed to warm to ambient temperature, cooled to −20° C., and quenched sequentially with H2O (1.1 mL), 15% NaOH (1.1 mL), and H2O (3.3 mL). The mixture was filtered through Celite, and the filtrated was concentrated to give the title compound as an oil that was used directly in the next step.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34]>>[OH:20][C:16]1[CH:17]=[C:18]2[C:13]([CH2:12][CH2:11][CH:10]([N:9]([CH2:21][CH2:22][CH3:23])[CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:33]([C:25]4[NH:24][C:32]5[C:27]([CH:26]=4)=[CH:28][CH:29]=[CH:30][CH:31]=5)=[O:34])[CH2:3][CH2:2]3)[CH2:19]2)=[CH:14][CH:15]=1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: CCCN(CCN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1)C1CCc2ccc(O)cc2C1
Yield: 84.8 %

Procedure:
Compound 40c was prepared following Procedure G using 39a (100 mg, 0.32 mmol) and indole-2-carboxylic acid (61 mg, 0.38 mmol) to give 40c (125 mg, 86%) after column chromatography. 1H NMR (400 MHz, CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.42-1.64 (m, 3H), 1.94 (brs, 1H), 2.51-2.75 (m, 14H), 2.88-2.96 (m, 1H), 3.95 (brs, 4H), 6.53 (brs, 1H), 6.59-6.61 (m, 1H), 6.75 (s, 1H), 6.90 (d, 1H, J=12.0 Hz), 7.11-7.18 (m, 1H), 7.22-7.26 (m, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.62 (d, 1H, J=8.0 Hz), 9.72 (s, 1H). The free base of 40c was converted into HCl salt. m.p. 203-205° C. Anal. [C28H36N4O2.2HCl.1.2H2O] C, H, N.
Reaction SMILES: C(O[C:4](=[O:16])[CH:5]([N:11]=[CH:12][N:13](C)C)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:17]N>C(O)C>[CH2:9]([O:8][C:6]([CH:5]1[C:4](=[O:16])[NH:17][N:13]=[CH:12][NH:11]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(N=CN(C)C)C(=O)OCC
Reactant: NN
Solvent: CCO
Product: CCOC(=O)C1NC=NNC1=O
Temperature: 60 °C
Yield: 44.9 %

Procedure:
2-(Dimethylamino-methyleneamino)-malonic acid diethyl ester (1 g, 4.34 mmol) was dissolved in ethanol (6.5 ml) and the mixture was heated to 60° C. Hydrazine (1M solution in THF, 5.5 ml, 5.52 mmol) was added dropwise during a period of 30 min and the mixture was heated to reflux for another 30 min. The reaction mixture was then cooled to 0° C. for 1 h and the precipitate that formed was filtered off. The filtrate was evaporated and ethyl acetate/methanol 4:1 (16 ml) was added to the oily residue. The suspension that formed was again filtered and the filtrate was evaporated. The remaining residue was triturated with ethyl acetate (9 ml) and the light brown solid was filtered off. The filtrate was again evaporated, the remaining solid triturated with a small amount of ethyl acetate and the resulting light brown solid was filtered off and combined with the first batch to give the title compound (333 mg, 1.95 mmol, 45%). MS: m/e=172.1 [M+H+].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:16]S(C(C)(C)C)=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][N:5]=1.[ClH:23].CCOCC>CO>[ClH:23].[ClH:23].[NH2:16][C@@H:3]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:13])[F:14])=[CH:6][N:5]=1)[CH2:2][OH:1]
Reactant: CC(C)(C)S(=O)N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Yield: 100 %

Procedure:
To a solution of N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}-2-methylpropane-2-sulfinamide (3.84 g, 11.3 mmol) and methanol (50 ml) was added 2.0N HCl in ether (45.1 ml, 90 mmol). The reaction was stirred for an hour and concentrated to give (2S)-2-amino-2-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanol dihydrochloride as a white foam (3.49 g, 100%). MS (Electrospray): m/z 237.1 (M+H). To a 100 ml round bottom flask equipped with a magnetic stir bar were added 4-cyclopropylphenylacetic acid (1.79 g, 10.2 mmol), (2S)-2-amino-2-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanol dihydrochloride (3.14 g, 10.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.34 g, 12.2 mmol), 1-hydroxy-7-azabenzotriazole (1.66 g, 12.2 mmol) and triethylamine (4.25 ml, 30.5 mmol) into 68 ml of dimethylformamide. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was washed with brine (3×50 ml) and extracted with ethyl acetate (3×70 ml). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give an oil. Purification by flash chromatography (SiO2, 50-100% EtOAc/Hexanes, gradient) gave 2-(4-cyclopropylphenyl)-N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a light yellow solid (3.00 g, 75%); 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=2.4 Hz, 1H), 7.42 (dd, J=2.4 Hz and 6.8 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 2H), 7.01 (d, J=6.4 Hz, 2H), 5.07-4.99 (m, 1H), 4.63 (q, J=6.4 Hz, 2H), 3.82-3.79 (m, 2H), 3.54 (s, 2H), 1.89-1.84 (m, 1H), 0.92 (m, 2H), 0.64 (m, 2H); MS (Electrospray): m/z 395.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH2:23]3)=[CH:18][CH:17]=2)[C@@H:10]([CH3:39])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.CO>[CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:23]3)=[CH:18][CH:17]=2)[C@@H:10]([CH3:39])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN1CCc2ccc([C@H](c3cccc(OC)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc([C@@H](c2ccc3c(c2)CN(CC(=O)O)CC3)N2C[C@H](C)N(Cc3ccccc3)C[C@@H]2C)c1
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a solution of the compound of Example 104 (0.85 g) in dioxan (20 ml) and methanol (10 ml) was added an aqueous solution of sodium hydroxide (2N, 5 ml). After 16 hours, the pH of the reaction was adjusted to pH5 using 1N aqueous hydrochloric acid solution and the solvent removed under reduced pressure. The crude product was purified on silica gel, eluting with a solvent gradient of 90:10:2 to 80:20:3 dichloromethane: methanol:ammonia solution. The fractions containing the product were pooled and the solvent removed under reduced pressure. The residue was taken up in a mixture of water and 1 drop of aqueous ammonium hydroxide solution and freeze-dried to give the title compound (0.65 g, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:16][C:17]1[S:18][C:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:20]([OH:22])[N:21]=1.P(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:16][C:17]2[S:18][CH:19]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C:20](=[O:22])[N:21]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Reactant: Nc1nc(O)c(-c2ccc(Cl)cc2)s1
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(NC1=NC(=O)C(c2ccc(Cl)cc2)S1)c1cc(Br)c2cccnc2c1O
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (0.268 g) of Preparation 2 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole (0.227 g) in 50 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.069 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from HOAc to yield 0.055 g of the title product as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])[CH3:2].C(OCC)C.[CH:19]1([Mg]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([OH:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cl[Mg]C1CCCC1
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(O)(c1ccccc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
Into a solution of 23.5 g of phenylglyoxylic acid ethyl ester in 200 ml of tetrahydrofuran, a diethyl ether solution of cyclopentyl magnesium chloride was added dropwise under ice cooling, followed by 30 minutes' stirring at the same temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction product was extracted with ethyl acetate, washed with saturated saline solution, and dried over anhydrous magnesium sulfate. Distilling the solvent off, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1 to 20/1). Thus 11 g of 2-cyclopentyl-2-hydroxy-2-phenylacetic acid ethyl ester was obtained, which was dissolved in 40 ml of methanol. To the solution 20 ml of 4N sodium hydroxide solution was added at room temperature, followed by 2 hours' stirring at the same temperature, and 1 hour's stirring at 50° C. Distilling the methanol off under reduced pressure, the aqueous layer was rendered weakly acidic with 4N hydrochloric acid and then extracted with ethyl acetate. The extract was washed with saturated saline solution, dried over anhydrous sodium sulfate and removed of the solvent by distillation. The resulting solid was washed with diethyl ether/hexane=1/1, and 8.7 g of 2-cyclopentyl-2-hydroxy-2-phenylacetic acid was obtained, which was dissolved, together with 11.6 g of cinchonidine, in 1.5 liters of toluene under heating, and the solution was cooled off to room temperature consuming about 4 hours. The white needles whereby precipitated were once again dissolved in 900 ml of toluene and cooled off to room temperature consuming about 4 hours. Recovering the precipitated white, acicular crystals by filtration, 8.0 g of (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetic acid cinchonidine salt was obtained. The salt was dissolved in a mixture of diethyl ether and 1N hydrochloric acid, and the organic layer was washed with water and then with saturated saline solution, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 3.0 g of the title compound was obtained as a white solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]([O:15]CC)=O)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]([NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:15])=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1n[nH]cc1-c1cccc(F)c1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1n[nH]cc1-c1cccc(F)c1
Yield: 64.6 %

Procedure:
4.6 q (19.64 mmol) of ethyl 4-(3-fluorophenyl)-3-pyrazolecarboxylate were reacted with t-butyl (2-aminoethyl)carbamate in an analoqous manner to that described in Example 16. Chromatoqraphy of the crude product and recrystallization from ethyl acetate/hexane yielded 4.4 g (64.6%) of t-butyl [2-(4-(3-fluorophenyl)-3-pyrazolecarboxamido)ethyl]carbamate as white crystals, melting point 175°-176°.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>C(#N)C>[C:13]([O:16][CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)c1coc(CBr)n1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1coc(COC(C)=O)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
9.5 g (10.80 mmol) of ethyl 2-(bromomethyl)oxazole-4-carboxylate are dissolved in 135 mL of acetonitrile. 9.96 g (101.47 mmol) of potassium acetate are added and the medium is stirred at room temperature for 14 hours.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].[Cl:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([S:16](Cl)(=[O:18])=[O:17])=[C:11]([CH3:20])[CH:10]=1>>[CH:1]([N:4]([S:16]([C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([Cl:8])=[CH:10][C:11]=1[CH3:20])(=[O:17])=[O:18])[CH2:5][CH2:6][O:7][S:16]([C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([Cl:8])=[CH:10][C:11]=1[CH3:20])(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Reactant: CC(C)NCCO
Product: Cc1cc(S(=O)(=O)OCCN(C(C)C)S(=O)(=O)c2cc(C)c(Cl)cc2C)c(C)cc1Cl

Procedure:
The title compound was prepared from 2-isopropylamino ethanol and 4-chloro 2,5-dimethylphenylsulfonylchloride using the method described in Description 1.