Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][N:6]=1)=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].[I-].[K+].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])=[N:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=1
Reactant: COc1cnc(C(=O)CBr)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(C(=O)CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.8 %

Procedure:
To 570 mg of 2-bromo-1-(3-chloro-5-methoxypyridin-2-yl)ethanone in 10 ml of N,N-dimethylformamide, 800 mg of potassium phthalimide and 36 mg of potassium iodide were added, and the mixture was stirred at 80° C. for 5 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 20 ml of water and extracted with ethyl acetate (40 ml×1), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 0.12 g of the desired product as white crystals.
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2].O[N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([O:14][N:34]2[C:35](=[O:44])[C:36]3=[CH:43][CH:42]=[CH:41][CH:40]=[C:37]3[C:38]2=[O:39])=[O:13])[CH2:8][CH2:7]1)#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: N#CC(CCN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: N#CC(CCN1CCC(C(=O)ON2C(=O)c3ccccc3C2=O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
2.12 Grams of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid are dissolved in 65 ml. of redistilled N,N-dimethylformamide by warming to about 60°C. To the warm solution is added, with stirring, .82 gram of N-hydroxyphthalimide, followed by 1.16 grams of dicyclohexylcarbodiimide. The resultant mixture is stirred at room temperature under calcium chloride, then cooled and filtered. The filtrate is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over potassium carbonate and partially concentrated until a precipitate forms. Filtration and repeated crystallizations of the precipitate from a mixture of chloroform and hexane affords N-[1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carbonyloxy]phthalimide, melting at about 156.5°-157.5°C. The product has the formula ##SPC4##
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH3:50])[C:22]([C:24]5[S:28][C:27]([NH:29]C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)=[N:26][C:25]=5[CH3:49])=[O:23])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:51])[N:7]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[F:59])[C:6]2=[O:60])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]([CH3:50])[C:22]([C:24]5[S:28][C:27]([NH2:29])=[N:26][C:25]=5[CH3:49])=[O:23])=[CH:19][CH:20]=4)[NH:10][C:9]=3[C:8](=[O:51])[N:7]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[F:59])[C:6]2=[O:60])[CH2:3][CH2:2]1
Reactant: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)sc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
A solution of 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (74.0 mg, 0.09 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with trifluoroacetic acid (1.0 mL). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was treated with triethylsilane (16 μL, 0.10 mmol). The reaction was concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 2-amino-4-methyl-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (3.0 mg, 5.8%) as a white solid: (ES)+-HRMS m/e calcd for C29H28N7O3SF (M+H)+ 574.2031, found 574.2035.
Reaction SMILES: [CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:21]=[C:22]([CH2:28][C:29]([OH:31])=[O:30])[CH:23]=[N:24][C:25]=2[O:26]C)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:36][CH2:37]O>C(Cl)Cl.O>[CH2:36]([O:31][C:29](=[O:30])[CH2:28][C:22]1[CH:23]=[N:24][C:25]([OH:26])=[C:20]([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:19])[F:17])=[CH:15][C:10]=2[CH2:9][N:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:7][CH3:8])[CH:21]=1)[CH3:37]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)cnc1OC)C(=O)C1CC1
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1cnc(O)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of (5-{2-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-methoxy-pyridin-3-yl)-acetic acid (0.099 g, 0.22 mmol) in EtOH (1 mL) was added thionyl chloride (0.16 mL, 2.19 mmol), and the reaction was stirred at 80° C. overnight. The mixture was diluted with CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give (5-{2-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-hydroxy-pyridin-3-yl)-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 3, Step 7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:19])([C:14]1[NH:15][CH2:16][CH2:17][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCOCC1>[C:20]([N:18]1[CH2:17][CH2:16][N:15]=[C:14]1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([OH:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:22])[CH3:21]
Reactant: OC(C1=NCCN1)(c1ccccc1)c1ccccn1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCN=C1C(O)(c1ccccc1)c1ccccn1
Temperature: 60 °C

Procedure:
Dissolve 12.8 g. of 2[(2-pyridyl)hydroxybenzyl] imidazoline in 25 ml. of dioxane and, with vigorous stirring, slowly add 2.4 ml. of acetic anhydride in a drop-wise fashion. After each 0.5 ml. addition warm the solution to 60° C for 5 min. and then cool the solution to 20° C before adding additional anhydride. Continue the stirring for 20 hours, filter the precipitated acetate salt and concentrate the resulting filtrate to about 10 mls. Recrystallize the desired product from alcohol to yield 1-acetyl-2[(2-pyridyl)-hydroxybenzyl]imidazoline, m.p. 150°-153° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]#[N:21])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (996.2 mg, 3.12 mmol) was dissolved in Et2O (33 mL) and cooled to 0° C. LAH (12.49 mL of a 1 M solution in Et2O, 12.49 mmol) was added dropwise by syringe. After stirring at 0° C. for 10 minutes, the reaction was warmed to room temperature and stirred at room temperature for 6 hours. The reaction was then quenched by slow dropwise addition of 1.5 mL of H2O (vigorous evolution of gas), followed by 1.5 mL of 30% NaOH, followed by 3.0 mL of H2O. The resulting gelatinous precipitate was washed with 5×20 mL of CH2Cl2; the organic washes were dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography with 2% MeOH/CH2Cl2 containing 0.1% Et3N afforded 1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine. Rf=0.30 (10% MeOH/CH2Cl2). LCMS=324.3 (M+1)+. 1H NMR. (CDCl3, 500 MHz) δ 7.77 (s, 1H), 7.55 (d, J=6.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.25 (dd, J=8.3, 2.1 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.66-3.74 (m, 5H), 2.91 (m, 1H), 1.26 (d, J=6.9 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])=[CH:5][CH:4]=1.[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([Cl:34])[CH:26]=1)=[S:23])[NH2:21]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:21][NH:20][C:22]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([Cl:34])[CH:26]=3)=[S:23])[CH3:17])[C:13]=2[OH:14])=[CH:5][CH:4]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1)c1csc(-c2ccc(C(F)(F)F)cc2)c1O

Procedure:
From 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonylthiophene (50.0 mg, 0.17 mmol) and 4-hydrazinocabonothioylamino-2-chlorobenzoic acid (42.9 mg, 0.17 mmol), the desired product was obtained in the same manner as in Synthetic Example 118 as a pale yellow solid (58.3 mg, yield 65%).
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([O:8]/[CH:9]=[C:10]2/[C:11](=[O:24])[N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][CH2:15][CH2:16]/2)[CH:3]=1.Cl>ClCCl>[CH3:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([O:8]/[CH:9]=[C:10]2/[C:11](=[O:24])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16]/2)[CH:3]=1
Reactant: CC1=CC(O/C=C2\CCCCN(C(=O)OC(C)(C)C)C2=O)OC1=O
Agent: Cl
Solvent: ClCCl
Product: CC1=CC(O/C=C2\CCCCNC2=O)OC1=O
Reaction time: 0.5 h

Procedure:
Tert-butyl (3E)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-2-oxo-azepane-1-carboxylate I-13b (0.55 g) was solved in dichloromethane (20 mL) and hydrogen chloride (2.0378 mL, 4M in dioxane) was added dropwise. After 30 min., dichloromethane was added and the reaction mixture was washed with sat. NaHCO3. The aqueous layer was extracted once with dichloromethane, the organic layers were combined, dried over Na2SO4 and the solvent was evaporated to give the crude as a yellow solid. The residue was triturated in tertbutylmethylether and the solid was filtered and dried to give (3E)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]azepan-2-one Ia-13 (0.245 g, 63%) as a white solid. LCMS (Method D): 0.67 min; ES+238 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]([CH:23]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:31](=[O:33])[CH3:32]>O1CCCC1>[CH2:13]([O:20][C:21]([C:23]1([CH:31]([OH:33])[CH3:32])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC=O
Reactant: CC1(C)COC(C(=O)OCc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)C1(C(=O)OCc2ccccc2)COC(C)(C)CO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of N,N-diisopropylamine (530 mg, 0.73 mL, 5.25 mmol) in anhydrous tetrahydrofuran (4 mL) was stirred at −78° C. under nitrogen. n-Butyl lithium (2.1 mL, 5.25 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. A solution of 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid benzyl ester (870 mg, 3.5 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was stirred at −78° C. for 20 min. Acetaldehyde (462 mg, 0.6 mL, 10.5 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 6:1 to 0:1 followed by silica gel chromatography using iso-hexanes/ethyl acetate 3:1 to 0:1 to the title compound (400 mg, 40%) as an oil and as a 2:1 mixture of diastereoisomers. LCMS (m/z) 295.1 [M+H], Tr=2.11 min.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:7]=1)=[O:5].[CH2:28]1[O:37][C:36]2[C:31](=[CH:32][C-:33]=[CH:34][CH:35]=2)[O:30][CH2:29]1.[Mg+2].[Br-]>C1COCC1>[O:30]1[C:31]2[CH:32]=[CH:33][C:34]([C:4]([C:6]3[C:15](=[O:16])[C:14]4[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=4)[N:8]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)[CH:7]=3)=[O:5])=[CH:35][C:36]=2[O:37][CH2:28][CH2:29]1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2nc(C)c(C)cc2c1=O
Reactant: [c-]1ccc2c(c1)OCCO2
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc4c(c3)OCCO4)c(=O)c3cc(C)c(C)nc32)n1
Yield: 35.4 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 were used with 100 mg (0.273 mmol) of 6,7-Dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl amide, 1.2 mL (0.60 mmol, 0.5M solution in tetrahydrofuran) of 3,4-(ethylenedioxy)phenylmagnesium bromide, and 1 mL of THF. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to afford 42.7 mg of 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-6,7-dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,8]naphthyridin-4-one. LC-MSD, m/z for C26H23N3O4 [M+H]: 442.17 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.9 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH3:15])=[CH:5][C:6]2[S:10](=[O:12])(=[O:11])[N:9]=[CH:8][C:7]=2[CH:13]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20]>[OH-].[Na+].C(O)C>[Cl:20][CH2:19][CH2:18][CH2:17][N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[C:4]([O:14][CH3:15])=[CH:5][C:6]=2[S:10]1(=[O:12])=[O:11]
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1OC)S(=O)(=O)N=C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1OC)S(=O)(=O)N(CCCCl)C2

Procedure:
2.4 gm (10.5 millimols) of the compound obtained in step (d) were dissolved in a mixture of 15 ml of an aqueous 2.5% sodium hydroxide solution and 30 ml of ethanol, and the solution was refluxed for 8 hours after addition of 10 ml of 3-bromo-1-chloro-propane. The reaction mixture was thereafter evaporated to half its volume, diluted with water and extracted with chloroform. After drying of the organic phase it was evaporated in vacuo, and the desired product was obtained as a highly viscous oil. Rf -value (chloroform/methanol = 19/1: 0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Cl:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2ccccc2Cl)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2Cl)CC1)c1ccccc1
Yield: 78.2 %

Procedure:
0.14 g (0.00062 mol) of 1-(2-chloro-benzyl)-piperidin-4-ol and 0.17 ml (0.00123 mol) of triethylamine were dissolved in 6.2 ml of toluene, treated with 0.09 ml (0.000776 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1→1:2). 0.16 g (78%) of 1-(2-chloro-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][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.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.C(Cl)Cl>[N:19]1([CH2:18][CH2:17][O:1][CH2:2][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)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: ClCCN1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COCCN2CCCC2)CC1
Yield: 73.5 %

Procedure:
Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5 g, 0.023 moles), 1-(2-chloroethyl)pyrrolidine (7.82 g, 0.046 moles) and tetrabutylammonium bromide (0.741 g, 2.3 mmol) were heated in toluene/water (1:1, 60 mL) to 90° C. overnight. The reaction mixture was diluted with DCM (100 mL), washed with water (100 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient from DCM to 90/10 DCM/methanol to afford tert-butyl 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine-1-carboxylate (5.28 g). LCMS [M+H]+=313.2
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[O:25]=[C:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[N:27]2[CH2:28][CH2:29][CH2:30][C:26]2=[O:25])=[CH:11][C:12]=1[F:17]
Reactant: O=C(O)c1ccccc1N1CCCC1=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: Cl
Product: O=C(NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1)c1ccccc1N1CCCC1=O

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-(2-oxopyrrolidin-1-yl)benzoic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26]C1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C=CC=C(OC)N=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([O:26][CH3:25])[N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Agent: COc1cccc(Br)n1
Product: COc1cccc(-c2ccc(-c3nc4ccccc4o3)cc2OC)n1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) was reacted with 2-bromo-6-methoxypyridine (65 μL, 0.57 mmol) to afford the desired 2-[3-methoxy-4-(6-methoxypyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.96–7.95 (m, 2H), 7.89 (s, 1H), 7.82–7.79 (m, 1H), 7.67–7.60 (m, 3H), 7.39–7.36 (m, 2H), 7.14–7.12 (m, 1H), 4.00 (s, 3H), 2.65 (s, 3H). MS (ESI) 333 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:42]>C(#N)C.C(OCC)(=O)C>[CH2:14]([O:13][C:12](=[O:21])[NH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:42])=[CH:4][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(NCCc1ccc(CO)cc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NCCc1ccc(CBr)cc1)OCc1ccccc1
Yield: 78.7 %

Procedure:
A solution of benzyl {2-[4-(hydroxymethyl)phenyl]ethyl}carbamate (1 g), triphenylphosphine (0.97 g) and carbon tetrabromide (1.2 g) in acetonitrile (1 ml) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-hexane (1:5, volume ratio)] and crystallized from hexane to give the title compound (0.96 g) as a colorless powder.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([CH3:17])=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[C:13]([CH3:17])=[CH:12][N:11]=1
Reactant: CCOC(=O)CN
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNc1nc(Cl)ncc1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Glycine ethyl ester hydrochloride (157 mg) was added to a solution of 2,4-dichloro-5-methylpyrimidine (184 mg) and diisopropylethylamine (486 μL) in acetonitrile (3 mL) while the solution was cooled with ice. The mixture was stirred at 40° C. overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1) to give 205 mg (81% yield) of the desired product as a white amorphous.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]([Li])(C)([CH3:9])[CH3:8].[CH:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:16](=[CH:17][C:18]3[O:22][CH2:21][O:20][C:19]=3[CH:23]=2)[CH:15]=1)=[O:13].[Cl-].[NH4+]>C1COCC1.CCCCC>[NH:5]1[CH:6]=[C:2]([C:12]([C:14]2[CH:26]=[CH:25][C:24]3[C:16](=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=3)[CH:15]=2)([OH:13])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:4]1
Reactant: Brc1c[nH]cn1
Reactant: [Li]C(C)(C)C
Reactant: O=Cc1ccc2cc3c(cc2c1)OCO3
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)C(O)(c1ccc2cc3c(cc2c1)OCO3)c1c[nH]cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-1H-imidazole (2.00 g) in THF (30 ml) was cooled to −78° C. A solution of tert-butyllithium in pentane (1.7 M; 22 ml) was added to the solution. The mixture was stirred at 0° C. for 1.5 h and then cooled to −78° C. 6-formylnaphtho[2,3-d][1,3]dioxol (3.00 g) in THF (30 ml) was added to the mixture. The mixture was allowed to room temperature and was stirred for 16 h. Ammonium chloride solution was added to the mixture and precipitate was collected, washed with water and ethyl acetate to give the titled compound (1.10 g) as a colorless solid.