Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:24])[C@@H:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]([CH3:24])[C@H:12]([CH2:13][OH:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OCc1ccccc1)[C@H](CO)CC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a mixture of (S)-2-((benzyloxycarbonyl)(methyl)amino)-4-tert-butoxy-4-oxobutanoic acid dicyclohexylamimonium salt (20 g, 0.0386 mol) and Et3N (7.90 mL, 0.0579 mol) in THF (500 mL) was added isobutyl chloroformate (6.05 mL, 0.0463 mol) at 0° C. The reaction mixture was stirred for 1 h, and filtered to remove TEA salt. To the filtrate was added a solution of NaBH4 (2.19 g, 0.0579 mol) in THF (50 mL) and water (100 mL) at 0-5° C. The reaction mixture was stirred at RT for 1 h and quenched with saturated NH4Cl solution. The reaction mixture was concentrated to remove most of THF and extracted with EtOAc (700 mL×3). The organic layers were washed with water, NaHCO3 and brine, dried over Na2SO4, and concentrated to give (S)-tert-butyl 3-((benzyloxycarbonyl)(methyl)amino)-4-hydroxybutanoate (10 g), which was used without further purification. LRMS (M+Na+) m/z 346.1.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][O:8][CH2:7]1)=O.[CH3:19][C:20]1[N:21]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CCO.O>[CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[C:6]2[CH2:7][O:8][CH2:9][CH2:10][C:11]=2[N:34]=[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])=[CH:26][CH:27]=2)[N:33]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: COC(C(=O)C1COCCC1=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COC(c1ccccc1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1COCC2
Temperature: 50 °C
Yield: 5.8 %

Procedure:
3-(2-Methoxy-2-phenylacetyl)dihydro-2H-pyran-4(3H)-one (100 mg, 0.40 mmol), 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) (87 mg, 0.40 mmol) and potassium carbonate (55.7 mg, 0.40 mmol) was slurrified in EtOH (4 mL) and heated to 50° C. for 15 h. DCM and water were added. The organic phase was separated, dried with MgSO4 concentrated and purified by preparative HPLC yielding 4-(methoxy(phenyl)methyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (10.0 mg, 5.7%). MS (ES+) m/z 428.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.P([O:15][C@H:16]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]1[OH:18])(O)(O)=O>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@:16]1([O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]1[OH:18])[OH:15]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: O=P(O)(O)O[C@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: OC[C@H]1O[C@](O)(n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O

Procedure:
One mL of a reaction solution consisting of 10 mM 6-chloropurine (Aldrich), 50 mM D-ribose-1-phosphate (22) prepared in Example 10, 0.1 mL of the ultrasonic enzyme homogenate from a purinenucleoside-phosphorylase producing strain prepared in Example 25 and 100 mM Tris-hydrochloride buffer (pH 7.5) was reacted at 50° C. for 20 hours. After completion of the reaction, HPLC analysis for the reaction solution under the conditions described below showed a peak of the title compound. A reaction inversion rate was calculated to be 62.4% after determining the concentration of 6-chloro-9-(β-D-ribofuranos-1-yl)purine in the post-reaction solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.CCO>[Pd].CCOC(C)=O>[NH2:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])cc(Cl)c2N1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-chloro-5-nitro-1,3-dihydro-2H-indol-2-one (6.1 g, 28.7 mmol) from Step 1 of this example was dissolved with stirring in 1:1 EtOH and EtOAc (287 ml). Palladium on carbon (10%, 1.8 g) was added and the slurry degassed, placed under an atmosphere of hydrogen (3×) and stirred at RT for 3 hours. The mixture was filtered through CELITE, the filter cake washed with EtOAc (3×100 ml), the filtrates combined and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[N:18]=[N:17]1.N1CCCCC1>CO>[NH:16]1[C:20]2[CH:21]=[CH:22][C:23](/[CH:25]=[C:7]3/[C:8](=[O:13])[NH:9][C:10]4[C:6]/3=[CH:5][C:4]([O:3][C:2]([F:1])([F:14])[F:15])=[CH:12][CH:11]=4)=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: O=C1Cc2cc(OC(F)(F)F)ccc2N1
Reactant: O=Cc1ccc2[nH]nnc2c1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccc(OC(F)(F)F)cc2/C1=C\c1ccc2[nH]nnc2c1
Temperature: 60 °C
Yield: 23.3 %

Procedure:
A scintillation vial was charged with 5-(trifluoromethoxy)indolin-2-one (27 mg, 0.124 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (20 mg, 0.136 mmol), piperidine (2 uL, 0.012 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 2 hrs. The MeOH was removed in vacuo and the residue purified by column chromatography (silica gel, 95:4:1, CH2Cl2/MeOH/AcOH) to give the title compound as a yellow solid (10 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 8.04 (d, J=4.5 Hz, 1H), 8.02 (s, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.42 (s, 1H), 7.21-7.18 (m, 1H), 6.99 (s, 1H); MS ESI 347.0 [M+H]+, calcd for [C16H9F3N4O2+H]+ 347.08.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:6]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:24]1([CH2:23][CH2:22][CH2:21][O:20][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=2)[C:3]([OH:30])=[O:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(OCCCc2ccccc2)cc(OCCCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cc(OCCCc2ccccc2)cc(OCCCc2ccccc2)c1

Procedure:
A solution of 3.0 g (7.4 mmol) of 3,5-bis(3-phenylpropoxy)benzoic acid methyl ester and 15 mL (15 mmol) of 1N NaOH in 100 mL of methanol and 40 mL of dioxane was stirred at reflux for 16 hours. The solvents were removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil which was crystallized from methanol-water to give 2.56 g, mp 107°-109°) of 3,5-bis(3-phenyl-propoxy)benzoic acid.
Reaction SMILES: CN1C(=O)C2C(=CC=C(C(O)=O)C=2)N1.[CH3:15][O:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=2)[N:19](C(OCC)=O)[N:18]=1>>[CH3:15][O:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=2)[NH:19][N:18]=1
Reactant: CCOC(=O)n1nc(OC)c2cc(C(=O)OC)ccc21
Agent: Cn1[nH]c2ccc(C(=O)O)cc2c1=O
Product: COc1n[nH]c2ccc(C(=O)O)cc12

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 16, using 1-ethyl 5-methyl 3-methoxy-1H-indazole-1,5-dicarboxylate, the regioisomeric product formed in Step 3. +ESI (M+H) 193.1; 1H NMR (400 MHz, DMSO-d6, δ): 12.65 (br. s., 1H), 12.26 (s, 1H), 8.18 (s, 1H), 7.86 (dd, J=8.9, 1.5 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC(=O)[NH:27][CH2:28][CH2:29][NH2:30])(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:43].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:43].[ClH:43].[NH2:27][CH2:28][CH2:29][NH:30][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: CN1CCOCC1
Product: NCCNC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 60 °C
Yield: 77.6 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg, 1.00 mmol) obtained in Step 6 of Example 1, N-(2-aminoethyl)carbamic acid tert-butyl ester (240 mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg, 1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound III (206 mg, 54%).
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Rh]>[CH:2]1([CH2:1][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Rh]
Solvent: CO
Product: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Yield: 98.6 %

Procedure:
To a solution of 50.0 g of diethyl benzylmalonate in 100 ml of methanol under nitrogen is added 5.0 g of 5% rhodium on alumina. The mixture is hydrogenated in a Parr hydrogenator at 50 pounds per square inch of hydrogen for 16 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated under vacuum to give 50.5 g of diethyl (cyclohexylmethyl)propanedioate as a colorless oil. A 2.80 g sample of sodium hydride (60% in oil) is washed with hexane (decanted) under argon and 70 ml of dry tetrahydrofuran added. The mixture is cooled in an ice bath and 17.94 g of diethyl (cyclohexylmethyl)propanedioate added dropwise over 15 minutes. To the mixture (0° C. to 5° C.) is added dropwise 13.23 g of 2-bromo-1-(2-furanyl)ethanone in 40 ml of tetrahydrofuran. The cooling bath is removed and the mixture stirred at room temperature overnight. The solvent is removed under vacuum and 100 ml of ether added. The mixture is filtered through 240 g of silica gel in a 600 ml glass sintered funnel and the silica gel pad washed with 2 liters of ether. The filtrate is concentrated to 300 ml and is washed three times with 100 ml portions of 1M sodium bicarbonate and with 100 ml of brine. The organic layer is dried (MgSO4) and the solvent removed to give 26.0 g of a brown oil. This oil is chromatographed on silica by HPLC on a Waters-Prep 500 instrument with hexane-ethyl acetate (12:1) to give 16 g of diethyl(cyclohexylmethyl)[2-(2-furanyl)-2-oxoethyl]-propanedioate as a light yellow oil.
Reaction SMILES: N1C=CC([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:22]=3)[C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14]2)=CC=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.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.CCOC(C)=O>[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:22]=3)[C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:34]=1
Reactant: O=C1CCCCC(c2ccccc2-c2ccncc2)N1Cc1cccc(-c2nccs2)c1
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCCCC(c2ccccc2-c2cccnc2)N1Cc1cccc(-c2nccs2)c1
Temperature: 80 °C

Procedure:
A mixture of 7-(2-bromophenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one (preparation described in example 450; 50 mg; 0.11 mmol), commercially available pyridin-3-ylboronic acid (14 mg; 0.11 mmol), and Pd(PPh3)4 (7 mg; 0.006 mmol) in THF (2 ml), and aq. 2 M Na2CO3 (0.2 ml) was heated to 80° C., under nitrogen, for 24 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 440.15 g/mol.
Reaction SMILES: C([Li])CCC.C([NH:9]C(C)C)(C)C.[CH3:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2C=1.[F:23][C:24]([F:41])([F:40])[C:25](=[O:39])[CH2:26][C:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[O:37][CH3:38])([CH3:29])[CH3:28]>C1COCC1>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:9]=[C:14]1[CH2:13][C:25]([OH:39])([CH2:26][C:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[O:37][CH3:38])([CH3:29])[CH3:28])[C:24]([F:23])([F:40])[F:41]
Reactant: Cc1cc2ccccc2o1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1nc2ccccc2o1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution of diisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C. The reaction mixture was cooled to −78° C. and stirred for 15 minutes. A solution of 2-methylbenzofuran (48 mg, 0.4 mmol) in 2 mL anhydrous THF was added dropwise to this mixture. After the addition, the reaction mixture was stirred for 15 to 30 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100 mg, 0.4 mmol) (Example 1) was added as a solution in anhydrous THF (2 mL) in one portion, the cold bath was removed, and the reaction was stirred at room temperature for 12 hours. THF was evaporated under reduced pressure. Water (2 mL) was added to the residue and the mixture was extracted with three 5 mL portions of EtOAc. The extract was dried over magnesium sulfate. After evaporation, the residue was chromatographed on a silica gel column to provide 86 mg of the title compound as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:26]([CH2:27][CH3:28])=[N:25][N:24]=[N:23]3)[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:27]([C:26]1[N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:30])([CH3:29])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[N:23]=[N:24][N:25]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-n3nnnc3CC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
To a stirred mixture solution of 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.5 g, 3.7 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.3 g, 90%) as a off-yellow solid: LC/MS m/e calcd for C21H23N5O2 (M+H)+: 378.45, observed: 378.2.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3]1.CCN(CC)CC.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH:2]1[CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CC1CN(c2ccc(C=O)cc2)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
A solution of 4-(3-methylpiperazin-1-yl)benzaldehyde (1.0 g, 4.89 mmol) in methylene chloride (15 mL) was cooled to 0° C. and treated with Et3N (0.68 mL, 4.89 mmol), followed by acetyl chloride (0.34 mL, 4.89 mmol). The resulting solution was stirred at 0° C. for 20 minutes and then concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% of EtOAc/CH2Cl2, to afford 4-(4-acetyl-3-methylpiperazin-1-yl)benzaldehyde (0.88 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2([CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[CH2:10][CH2:9]2)[CH:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH2:36])[N:27]=1)=[O:25]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[N:36]=[CH:13][C:12]([OH:19])([C:15]([F:18])([F:16])[F:17])[CH2:11][C:8]2([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:20][CH3:21])[CH2:10][CH2:9]2)[N:27]=1)=[O:25]
Reactant: COc1ccc(F)cc1C1(CC(O)(C=O)C(F)(F)F)CC1
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(N=CC(O)(CC3(c4cc(F)ccc4OC)CC3)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 306 mg (1.2 mmol) of 5-{3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propanal is reacted with 170 mg (0.84 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 4.0 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0-70%), 204 mg (49% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[CH2:19]([NH2:21])[CH3:20].C(OCC)C>C(O)C>[CH2:19]([NH:21][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1)[CH3:20]
Reactant: CCN
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Solvent: CCO
Solvent: CCOCC
Product: CCCOc1ccccc1-c1nc(NCC)cc(=O)[nH]1

Procedure:
4-Chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.66 g) and ethylamine in ethanol (33%, 20 ml) was heated at 90° C. in a pressure vessel for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which solidified on trituration with diethyl ether. The residue was recrystallised from isopropanol: diethyl ether, washed with water and recrystallised from isopropanol:water to yield the title compound, 0.47 g, m.p. 187°-8° C.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[S:16]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:18])(=[O:17])[CH3:15]
Reactant: CC(C)OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCOS(C)(=O)=O
Reaction time: 2 h

Procedure:
Alternately, combine 2-isopropoxyethanol (5.0 g, 48 mmol) and dichloromethane (50 mL). Cool in an ice bath. Add triethylamine (10.7 g, 105 mmol). Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with 1 M hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Distill the residue at reduced pressure to give 2-(isopropoxy)ethyl mesylate.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([C:14]#[N:15])[C:5](=O)[N:6]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH:7]=1.[OH2:17].[NH2:18][NH2:19]>C(O)C>[NH2:15][C:14]1[C:4]2[C:5](=[O:17])[N:6]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH:7]=[C:2]([Br:1])[C:3]=2[NH:19][N:18]=1
Reactant: NN
Reactant: CC(C)[C@H](C)n1cc(Br)c(Cl)c(C#N)c1=O
Reactant: O
Solvent: CCO
Product: CC(C)[C@H](C)n1cc(Br)c2[nH]nc(N)c2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of 5-bromo-4-chloro-1-((2S)-3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step F (19.2 g) in ethanol (200 mL) was added hydrazine monohydrate (9.5 g), and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was allowed to be cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in a mixed solvent of ethyl acetate-tetrahydrofuran-water. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane, and then ethyl acetate/methanol), and recrystallized from (ethyl acetate/diisopropyl ether) to give the title compound (15.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14]>ClC(Cl)C>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([C:21]1[CH:20]=[C:19]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:18]([OH:27])=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:22]=1)=[O:5]
Reactant: Cc1cc(C)c(C(=O)Cl)c(Cl)n1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CC(Cl)Cl
Product: Cc1cc(C)c(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Yield: 81.9 %

Procedure:
The similar procedure in reference example 1 by using 12.2 g of 2-chloro-4,6-dimethylnicotinoyl chloride, 14.8 g of 2,6-di-tertiary butylphenol and 18.8 g of anhydrous stannic chloride in dichloroethane is performed and the obtained crude product is recrystallized from hexane to give 18.3 g of 4-(2-chloro-4,6-dimethylnicotinoyl)-2,6-di-tertiary butylphenol as pale yellow crystals, melting at 129°-132° C. According to the similar manner as the above Reference Examples, 4-(2-chloro-6-isopropylnicotinoyl)-2,6-di-tertiary butylphenol, melting at 109°-110° C. is prepared.