Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[C@@H:24]2[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[N:18]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([N:18]2[C@@H:19]3[C@H:24]([CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:15][CH2:16][CH2:17]2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(N2CCN(Cc3ccccc3)[C@H]3CCCC[C@@H]32)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Clc1ccc(N2CCN[C@H]3CCCC[C@@H]32)cc1
Yield: 52.8 %

Procedure:
1-chloroethyl chloroformate (229 μL, 2.10 mmol) was added to a methylene chloride (6.5 mL) solution of (4aS,8aS)-1-benzyl-4-(4-chlorophenyl)decahydroquinoxaline (0.650 g, 1.91 mmol) with ice-cooling and stirring. The mixture was stirred at room temperature for 15 hours, and the reaction mixture was then concentrated under reduced pressure. The obtained residue was dissolved in methanol (6.5 mL), and this solution was stirred for 1 hour under reflux. The solvent was distilled off from the reaction mixture. To the obtained residue, acetone (5 mL) was added, and the mixture was stirred. The deposited crystal was collected by filtration. The obtained crystal was washed with acetone (1 mL) and then dried to obtain (4aS,8aS)-1-(4-chlorophenyl)decahydroquinoxaline (253 mg, yield: 53%) in a white powder form.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=[C:2]2[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Cl)c2ccc(C)c(F)c2n1
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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C)c(F)c2n1
Temperature: 75 °C
Yield: 80.9 %

Procedure:
Methyl 4-chloro-8-fluoro-7-methylquinoline-2-carboxylate (7-8, 993 mg, 3.91 mmol), (4-Fluorophenyl)boronic acid (575 mg, 4.11 mmol), and Pd(Ph3P)4 (226 mg, 0.196 mmol) were dissolved in degassed toluene (25 mL). Degasses EtOH (2.7 mL) was added followed by degassed 2M aq. Sodium Carbonate (4.31 mL, 8.61 mmol). The reaction was heated at 75° C. overnight then quenched with water and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was triturated with ether to afford Methyl 8-fluoro-4-(4-fluorophenyl)-7-methylquinoline-2-carboxylate (7-9, 991 mg, 81% yield) as a tan solid, LCMS shows the compound is 89% pure, LRMS m/z (M+H)+ 314.1 found, 314.0 required.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13](F)[N:12]=2)[N:9]=[CH:8][C:7]=1[C:23]#[N:24].Cl>C(OC)(C)(C)C>[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([O:2][CH3:1])[N:12]=2)[N:9]=[CH:8][C:7]=1[C:23]#[N:24]
Reactant: CO
Reactant: N#Cc1cnn(-c2nc(F)c(C(F)(F)F)cc2Cl)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1nc(-n2ncc(C#N)c2N)c(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
5 ml of methanol were added to a suspension of 0.23 g (0.0092 mol) of 95% strength sodium hydride in 75 ml of methyl tert-butyl ether at 20° C. in the course of 10 minutes and the mixture was stirred for 25 minutes to give a clear solution. 3 g (0.0098 mol) of 5-amino-4-cyano-1-(3-chloro-6-fluoro-5-trifluoromethyl-2-pyridyl)pyrazole (Active Compound Example No. 2a.001) in 50 ml of methyl tert-butyl ether were then added with stirring and the mixture was stirred at 25° C. for 2 hours. About 50 g of ice and 100 ml of 1N hydrochloric acid were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution, dried and filtered through silica gel. After concentrating, stirring with ether/pentane, filtering off with suction and drying, 2.4 g (77% of theory) of the title compound of m.p. 135-139° C. were obtained (Active Compound Example No. 2c.001).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[CH:4][N:3]=1.[C:11](OC(OCC)OCC)(=O)C>>[CH3:10][N:9]1[C:7](=[S:8])[N:6]2[N:5]=[CH:4][N:3]=[C:2]2[N:1]=[CH:11]1
Reactant: CCOC(OCC)OC(C)=O
Reactant: CNC(=S)n1ncnc1N
Product: Cn1cnc2ncnn2c1=S
Yield: 88 %

Procedure:
The synthesis method of Example 55 was applied. The compound (1.49 g) obtained in Example 29 and diethoxymethyl acetate (12 ml) were used as reagents. The mixture was reacted at 75° C. for 2 hours to give 1.39 g of white crystals (yield 88%). The crystals were subjected to recrystallization from acetone to give white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH:25][C:26](=[O:50])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:38]5[CH:39]=[CH:40][C:41]([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=6)=[CH:42][C:37]5=[N:36][CH:35]=4)=[CH:30][C:29]=3[F:49])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.C1COCC1>[F:49][C:29]1[CH:30]=[C:31]([C:34]2[N:38]3[CH:39]=[CH:40][C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)=[CH:42][C:37]3=[N:36][CH:35]=2)[CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([NH:25][C:17]1[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=[C:15]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:51])[CH:16]=1)=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(NC(=O)Cc3ccc(-c4cnc5cc(-c6ccccn6)ccn45)cc3F)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccc(-c2cnc3cc(-c4ccccn4)ccn23)cc1F)Nc1cc(C(=O)N2CCNCC2)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Dissolve 4-(3-{2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetylamino}-5-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (0.76 g, 0.108 mmol) in 1:1 CH2Cl2 MeOH (20 mL) and add 2M HCl in THF (2 mL), then stir 2 hours and concentrate in vacuo. Load onto a Varian MegaElut® SCX cartridge (10 gram cartridge prewashed with methanol), rinse with methanol to remove impurities then elute crude product with 2 M NH3 in methanol. Concentrate this solution in vacuo then purify by silica gel chromatography (0%→10% 2 M NH3 Methanol:DCM) to give a yellow residue (0.400 g, 49% over 2 steps). MS (ES), m/z 603 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[C:21]([OH:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[C:23]([C:22]1[C:21]([OH:28])=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: N#Cc1cccc(N)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1O
Yield: 18.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 513 mg of 3-amino-2-hydroxybenzonitrile and 734 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 5 ml of pyridine and 5 ml of N,N-dimethylformamide. 257 mg of N-(3-cyano-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH:14]2[O:16][CH2:15]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1OCC1CO1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture consisting of 31.4 g of 4-fluoro-2-nitrophenol, 100 ml of epichlorohydrin, 9.1 g of sodium hydroxide, 40 ml of water, and 900 ml of ethanol was stirred at 80° C. for 10 hours. The reaction mixture was cooled to room temperature, and any insoluble matter was removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in a 1:1 mixed solvent of diethyl ether and hexane, washed with water and then with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography using a 3:1 mixture of chloroform and hexane as a developing solvent. The fraction containing the desired compound was concentrated to give 27.9 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[N:9]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])[CH2:29][CH2:28]2)[C:8]1=[O:43].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:19][CH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:34])[CH2:29][CH2:28]1)[C:8](=[O:43])[N:7]([CH2:6][C:5]1[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]2=[O:17]
Reactant: COc1ccc(Cn2c(=O)c3cc(CNC(=O)OC(C)(C)C)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Yield: 104 %

Procedure:
A solution of 0.102 g of benzyl 4-[3-(3,4-dimethoxybenzyl)-6-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 5.4 and 0.5 ml of TFA in 9.5 ml of DCM is stirred at AT for 2 h 00. A saturated NaHCO3 solution is added. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure to give 0.09 g of the expected product.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.CC(O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:20]1([CH2:1][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCCCC2)CC1
Yield: 92.7 %

Procedure:
To 1,1-dimethylethyl 4-formyl-1-piperidinecarboxylate (1.02 g, 4.78 mmol) in 1,2-dichloroethane (50 mL) was added sequentially, HOAc (6.00 mL, 1M in DCM, 6.00 mmol), piperidine (1.0 mL, 10.1 mmol) and sodium triacetoxyborohydride (1.60 g, 7.55 mmol). The reaction was stirred at rt for 2 hours at which time HOAc (1.00 mL, 1M in DCM, 1.00 mmol) and sodium triacetoxyborohydride was added. When complete by TLC the reaction was quenched with saturated NaHCO3 (150 mL) and extracted with DCM. The combined organic layer was washed with H2O, dried (MgSO4) and concentrated to provide the title compound (1.25 g, 4.43 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-0.91 (m, 2H), 1.29-1.35 (m, 11H), 1.38-1.46 (m, 4H), 1.59 (d, J=10.6 Hz, 3H), 2.00 (d, J=6.8 Hz, 2H), 2.21 (br. s., 4H), 2.62 (br. s., 2H), 3.85 (d, J=12.6 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Mg]Cl)(C)C.[Cl-].[Li+].[F:13][CH:14]([F:20])[C:15](OCC)=[O:16]>C1COCC1.C(OCC)(=O)C>[F:13][CH:14]([F:20])[C:15]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:16]
Reactant: CCOC(=O)C(F)F
Reactant: c1cscn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1nccs1)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
This procedure is based on literature, see: Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 2958. Thiazole (5.7 mL, 80 mmol) in THF (100 mL) was added to a stirred, cooled (0° C.) solution of isopropylmagnesium chloride-lithium chloride (1.18 M in THF, 74.9 mL, 88 mmol) in THF (75 mL) then the mixture was stirred at room temperature for 1 hour. Then the solution was cooled to −20° C. and ethyl difluoroacetate (9.29 ml, 88 mmol) was added. The mixture was stirred for 10 minutes at −20° C., then 10 minutes at room temperature. The mixture was diluted with ethyl acetate (200 mL), washed with aqueous ammonium chloride (saturated, 200 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chromatography on silica gel, 0-90% ethyl acetate in hexanes) to give 2,2-difluoro-1-(1,3-thiazol-2-yl)ethanone (12 g, 73.6 mmol, 92% yield) as a yellow oil. MS ESI: [M+H]+ m/z 164.0.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3C)c(C)nc12
Yield: 87.6 %

Procedure:
110 mg of 8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.28 mmol) and 122 mg of morpholine (1.4 mmol) are dissolved in 3.0 ml of THF and 182 mg of cesium carbonate (0.56 mmol) is added. The mixture is put in 4 ml vial with a Teflon® lined cap and heated at 110 C overnight. The reaction mixture is concentrated and applied to a silica-gel column chromatography column with hexane:EtOAc=3:1 eluent to give 98 mg of the title compound (88%). mass spectrum (m/e): 400 (M+1); 1H-NMR (CDCl3): δ 6.70 (s, 1H), 3.87 (t, 4H, J=4.8 Hz), 3.56 (t, 4H, J=4.8 Hz), 3.35 (m, 1H) 2.56 (s, 3H), 2.46 (s, 3H), 1.86 (m, 4H), 0.90 (t, 6H, J=7.6 Hz)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]>CCO.Cl>[N:1]1([CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of morpholine (80 g, 0.91 mol) and triethylamine (232 g, 2.29 mol) in EtOH (1750 ml) was added dropwise at 0° C. a solution of methyl 3-(bromomethyl)benzoate (252 g, 1.1034 mol) in absolute alcohol (250 ml). The mixture was stirred overnight at RT. Then the mixture was concentrated and the residue obtained was taken up in 1.5N HCl (3 L) then washed with diethyl ether (3 times) and ethyl acetate. The solution was neutralized with a 10% aqueous NaOH solution and basified up to pH=8 with a 10% aqueous NaHCO3 solution. The product was extracted with CHCl3, washed with water and brine then dried over Na2SO4. The solvent was removed and the crude was purified by column chromatography CHCl3/MeOH to give methyl 3-(morpholin-4-ylmethyl)benzoate (150 g, 70%) as brown liquid.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])C.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:28]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:7]([C:5](=[O:6])[C:4]([OH:3])=[O:27])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C#CCCCCCCCC
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1ccccc1Br
Product: CCCCCCCCC#Cc1ccccc1CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(=O)O

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl{(2-bromobenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate and dec-1-yne gave the title compound as a pale yellow oil. M−(LC/MS(ESI)): 472.0. HPLC (Condition A), Rt: 5.51 min (HPLC purity: 99.6%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OCCCNc1ccnc2cc(Cl)ccc12
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(CCCNc3ccnc4cc(Cl)ccc34)CC2)cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
The product of Preparation 2 (0.69 g, 0.00219 mol) and 1-(4-methoxyphenyl)piperazine (0.51 g, 0.00263 mol) were dissolved in THF (15 mL) and triethylamine (0.44 g, 0.00438 mol) was added. The reaction mixture was stirred and heated at reflux for 4 days. After cooling to room temperature, saturated NaHCO3 solution (30 mL) was added, and the mixture was extracted with chloroform (3×10 ml). The organic layer was dried over MgSO4 and evaporated. The resulting powder was dissolved in a mixture of methanol/ethyl acetate (1:3) (10 ml). After filtering, the solution was evaporated to give the title compound (0.09 g, 10%) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][Si](C(C)(C)C)(C)C)=[CH:9][CH:10]=2)[C:5]([N:20]2[CH2:24][CH2:23][C@@H:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:21]2=[O:33])=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([N:20]2[CH2:24][CH2:23][C@@H:22]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:21]2=[O:33])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)c3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)c3ccc(O)cc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (R)-1-[4-bromo-7-(tert-butyldimethylsilyloxy) naphthalen-1-yl]-3-(tert-butoxycarbonylamino)-2-oxopyrrolidine, as described above in Step H, (470 mg, 0.88 mmol) in THF (4 mL) was added TBAF (1.0 mL of a 1 M solution in THF, 1 mmol), dropwise. The mixture was stirred at ambient temperature for 30 min, then poured into saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (25 mL). The aqueous layer was extracted further with CH2Cl2 (2×25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—20% EtOAc to yield the desired phenol.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:41])[C@@H:28]2[CH2:32][C@H:31]([OH:33])[CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-]>ClCCl.CN(C)C1C=CN=CC=1>[O:13]([C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:41])[C@@H:28]2[CH2:32][C@H:31]([O:33][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (4.40 mL) and methanesulfonyl chloride (1.95 mL) was added to a cold (0° C.) stirred solution of cis-4-hydroxy-N-tert-butoxycarbonyl-L-proline 4-phenoxyphenylamide (C, 5.02 g) in dichloromethane (100 mL). The mixture was stirred at 0° C. for 2 hr and at room temperature for 45 min. Triethylamine (4.40 mL) and mehanesulfonyl chloride (1.95 mL) was added to the cold (0° C.) stirred mixture. The mixture was stirred at 0° C. to room temperature for 2 hr, and 4-dimethylaminopyridine (1.54 g) was added at 0° C. The mixture was stirred at room temperature for 1 hr and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (6.49 g).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.[Li+].[OH-]>O1CCOCC1>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OCCF)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a solution of methyl 4-(2-fluoroethoxy)benzoate (7.7 g, 38.85 mmol) in dioxane (100 mL) was added LiOH (2M, 39 mL). The reaction mixture was stirred at room temperature for 18 hours, and then concentrated in vacuo. The residue was dissolved in H2O (30 ml) and extracted with ether. Under cooling the aqueous was acidified with HCl (6N) and extracted with CHCl3. The organic extracts were dried over MgSO4. Evaporation and recrystallization from ethyl acetate and methylene chloride gave the title compound as a white solid (5 g, 71% yield); 1H NMR (400 MHz, DMSO-d6) δ 4.28 (m, 1H), 4.35 (m, 1H,) 4.68 (m, 1H), 4.80 (m, 1H), 7.04 (d, 2H), 7.89 (d, 2H); MS m/e (M−H)− 183.1; mp 203° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:4]1)[CH3:2].[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=[C:27]1S(C)(=O)=O.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:27]3[N:26]([CH2:25][CH2:24][O:23][CH3:22])[C:30]4=[N:31][CH:32]=[CH:33][CH:34]=[C:29]4[N:28]=3)=[CH:15][CH:14]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3CCOC)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a stirred solution of 4-(1-ethyl-6-fluoro-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (57.6 mg) in DMF (4 mL) was added NaH (60% in oil, 5.38 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (38.0 mg).