Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:17][CH3:18])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>[Pd]>[CH2:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:2][CH2:18][O:17][CH2:7][CH3:8]
Reactant: CCCCCCCCC(=O)OC
Reactant: OCC(O)CO
Agent: [Pd]
Product: CCCCCCCCCOCC(O)CO
Product: CCOCC
Temperature: 145 °C
Yield: 20 %

Procedure:
A stirred autoclave was charged, at room temperature, with 55.2 g (600 mmol) of glycerol, 51.6 g (30 mmol) of methyl pelargonate, 0.039 g (10 wt %) of camphosulfonic acid and 0.64 g (1 mol %) of Pd/C at 5%. The autoclave was then pressurized at 10 bar of dihydrogen gas H2, and then it was heated at 145° C. for 24 h, stirring vigorously. After 24 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was then filtered on a MILLIPORE® filter (a membrane filter) (0.45 μm) and was rinsed with absolute ethanol. The solvents were then evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×20 ml) and the CH2Cl2 was then evaporated at reduced pressure. 1-O-nonyl-glycerol ether was obtained by purification on a flash silica column with ethyl acetate/cyclohexane mixture 1/4 to 1/1 as eluent with an isolated yield of 20%.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:10]([O:11][CH3:12])[C@@H:9]([CH2:13][O:14][CH3:15])[O:8][CH:5]([O:6][CH3:7])[C@@H:4]1[OH:16].[CH3:17]O[C@H]1[C@H](O)[C@H](OC)COC1OC>>[CH3:1][O:2][C@H:3]1[C@H:10]([O:11][CH3:12])[C@@H:9]([CH2:13][OH:14])[O:8][CH:5]([O:6][CH3:7])[C@@H:4]1[OH:16].[CH3:17][O:16][C@@H:4]1[C@@H:3]([O:2][CH3:1])[C@H:10]([O:11][CH3:12])[C@@H:9]([CH2:13][O:14][CH3:15])[O:8][CH:5]1[O:6][CH3:7]
Reactant: COC[C@H]1OC(OC)[C@H](O)[C@@H](OC)[C@H]1OC
Reactant: COC1OC[C@@H](OC)[C@@H](O)[C@@H]1OC
Product: COC1O[C@H](CO)[C@@H](OC)[C@H](OC)[C@H]1O
Product: COC[C@H]1OC(OC)[C@H](OC)[C@@H](OC)[C@@H]1OC

Procedure:
When it is subjected to methanolysis (i.e., heated under reflux in 9% hydrochloric acid-dry methanol), it gives 1 mol each of methylgalactoside, methylarabinoside and methylglucuronide, and 2 mols of methylglucoside. A completely methylated compound (C77H132O29) obtained by methylation of soyasaponin A1 with methyl iodide, dimethyl sulfoxide and sodium hydride gives 1 mol each of methyl 3,4-di-O -methylglucopyranoside, methyl 3,4,6-tri-O -methylgalactopyranoside and methyl 2,4-di-O-methylarabinopyranoside, and 2 mols of methyl 2,3,4,6-tetra-O-methylglucopyranoside when subjected to methanolysis after reduction. It also gives 1 mol of 3,22,24-tri-O-methyl soyasapogenol A (C33H56O4).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:42][C:43](=[O:46])[CH2:44][NH2:45].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:45][CH2:44][C:43]([OH:46])=[O:42])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCC(=O)O)cc2)cc1
Reaction time: 12 h
Yield: 87.3 %

Procedure:
A solution of the product from Example 104A (0.065 g, 0.119 mmoles), glycine methyl ester hydrochloride (0.0300 g, 0.24 mmoles), and diisopropylethylamine (0.042 mL, 0.24 mmoles) in DMF (0.3 mL) was treated with EDAC (0.032 g, 0.167 mmoles) and HOBT (0.0225 g, 0.167 mmoles). The resulting mixture was shaken for 12 h. The crude products were diluted with diethyl ether, extracted with sat. NH4Cl, extracted with H2O (2×), rinsed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel. The product was dissolved in EtOH (0.5 mL) and THF (0.5 mL) and treated with 2N NaOH (1.0 mL) for 4 h. The resulting mixture was poured into 3N HCl and extracted with ethyl acetate (2×). The combined organics were rinsed with brine, dried (Na2SO4), and concentrated under reduced pressure. Purification by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column yielded the title compound (0.0625 g, 87%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 8.18 (t, 1 H), 7.23 (m, 9 H), 7.00 (m, 3 H), 6.86 (m, 4 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 3.73 (d, 2 H), 2.91 (s, 3 H), 2.79 (t, 2 H), 2.40 (m, 3 H), 2.39 (s, 3 H); MS (APCI) m/z 602 (M+H+).
Reaction SMILES: C([NH:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15](=[O:18])[CH2:16]Br)=[CH:9][N:8]=1)(=O)C(C)C.[CH3:19][C@@H:20]([NH2:31])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1.Cl>C(#N)C.CCOCC>[N:8]1[CH:7]=[CH:12][CH:11]=[C:10]([CH2:15][OH:18])[CH:9]=1.[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C@@H:15]([CH2:16][NH:31][C@H:20]([CH3:19])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[OH:18])=[CH:11][C:12]=1[C:13]#[N:14]
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)C(=O)Nc1ncc(C(=O)CBr)cc1C#N
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: C[C@H](Cc1c[nH]c2ccccc12)NC[C@@H](O)c1cnc(N)c(C#N)c1
Product: OCc1cccnc1

Procedure:
A solution of 0.5 g of 2-isobutyramido-3-cyano-5-(bromoacetyl)pyridine and 1.25 g of 1(R)-methyl-2-(1H-indol-3-yl)ethyl amine in 50 ml of dry acetonitrile under nitrogen is stirred for 30 minutes at room temperature. The reaction mixture is made acidic with gaseous hydrochloric acid and then diluted with ether. The solution is concentrated and the residue redissolved in methanol. The solution is cooled in an ice bath and treated slowly with sodium borohydride (0.4 g) for one hour. The pH of the solution is adjusted to approximately 6 with acetic acid and extracted with CH2Cl2. The combined organic extracts are backwashed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product is dissolved in 15 ml of methanol and treated with 0.7 g of KOH. The reaction mixture is heated at reflux for 2 hours and then partially concentrated. The solution is diluted with water and extracted with CH2Cl2. The combined extracts are backwashed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate prior to concentration. The residue is chromatographed on silica gel to give (R)-6-Amino-5-cyano-α-[[1(R)-methyl-2-(1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol and (S)-6-Amino-5-cyano-α-[[(1-(R)-methyl-2-(1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CO.Br[CH:16]([C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=1)[C:17]#[N:18]>[OH-].[Na+]>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:1][CH:16]([C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)[C:17]#[N:18])[NH:3][C:4]=2[CH:10]=1
Reactant: COc1c(C)cnc(C(Br)C#N)c1C
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc(SC(C#N)c3ncc(C)c(OC)c3C)[nH]c2c1
Yield: 58 %

Procedure:
To a solution of 2-mercapto-5-methoxybenzimidazole (15.1 g, 0.14 mole) dissolved in 40 ml of 8.4% sodium hydroxide, was added 170 ml of methanol, followed by bromo(4-methoxy-3,5-dimethyl-2-pyridyl)acetonitrile(21.4 g, 0.11 mole) at room temperature. The mixture was heated to reflux for 1 h under a nitrogen atmosphere. The resulting precipitate was removed by filtration and the methanol was evaporated. The residue obtained was extracted with chloroform, and the chloroform was washed 3 times with water and dried over magnesium sulfate. After evaporation of the solvent, the crude product was recrystallized from diethyl ether to give 22.6 g (90%) of the title compound as yellowish crystals: mp 193-197° C.; 1H NMR (CDCl3)δ 8.25 (s, 1H), 7.65 (dd, 1H), 7.30 (m, 1H), 6.90 (m, 1H), 6.30 (br s, 2H), 3.95 (s, 3H), 3.75 (s, 3H), 2.50 (s, 3H), 2.20 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.ClCCl.CCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([C:10]#[N:11])[CH2:12][CH:14]2[CH2:15][OH:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: ClCC1CO1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: N#C[C@]1(c2ccc(Cl)c(Cl)c2)CC1CO
Temperature: -25 °C
Yield: 407.9 %

Procedure:
3,4-Dichlorophenyl acetonitrile (3 g, 1.6 mmole) was dissolved in dry tetrahydrofuran (THF, 25 mL) under nitrogen atmosphere. The solution was cooled to −25° C. Soda amide (0.6235, 1.6 mmol) was added portion wise maintaining the temperature of the reaction mass −25° C. The reaction mixture was allowed to warm to room temperature and maintained for 2 hours. It was then cooled to −25° C. A solution of S-(+) epichlorohydrin (1.49 g, 1.6 mmol) in tetrahydrofuran (5 mL) was added drop wise at −25° C. followed by the portion wise addition of soda amide (0.6235, 1.6 mmol). The temperature of the reaction mass was then gradually raised to room temperature over a period of 8 hours. The reaction was monitored by TLC (dichloromethane/hexane (1:1)). The reaction mass was quenched with saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (3×50 mL).The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 4.0 g of crude oil. The crude oil was purified by column chromatography (silica gel, dichloromethane/hexane (9:1) to yield 1.58 g (40%) of product. 1H NMR: δ(300 MHz,CDCl3): 1.57-1.72(3H,m), 1.88-1.99 (1H,m), 3.72-3.79 (1H,dd, J=12.08,8.4 Hz), 4.06-4.12 (1H,dd, J=12.08,4.95 Hz), 7.13-7.17 (1H,m) 7.39-7.52 (2H,m).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[S:16][C:17]([F:20])([F:19])[F:18]
Reactant: c1cn[nH]c1
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 13.1 using (R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 15.2) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole to afford a yellow resin. UPLC-MS (Condition 3) tR=1.33 min, m/z=598.4 [M+H]+, m/z=596.5 [M−H]−.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[CH3:36][O:37]C1C=C(S)C=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:36][O:37][C:8]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(S)c1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1cccc(SCCCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 3-methoxy-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C([Li])CCC.Br[C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O>CCCCCC.O1CCCC1>[CH3:13][C:7]([CH3:14])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: BrCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)Cc1ccccc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
25 ml of a 1.6M solution of n-butyllithium in n-hexane were added dropwise to a solution of 5.3 ml (7 g, 36 mmol) of ethyl bromoisobutyrate in 20 ml of tetrahydrofuran at -75° to -70° C. The mixture was then warmed to -20° C., 6.42 ml (9.43 g, 54 mmol) of benzylbromide were added dropwise and the mixture was subsequently stirred at room temperature for a further 3 hours. Dilute sulfuric acid was then added to the reaction mixture and the mixture was extracted twice with ether. The organic phase was washed with water, dried over magnesium sulfate and concentrated in vacuo. The crude product (6.6 g) was purified by distillation.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:28]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=[CH:25][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7].C(N(CC)CC)C.Cl.C(OCC)(=O)C>CS(C)=O>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]2[CH:2]=[CH:3][C:4]3[C:5](=[CH:25][CH:26]=[C:27]([O:35][CH3:36])[C:28]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:6]2=[O:7])=[CH:16][CH:15]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccc(OCc3ccccc3)cc2)c1CCO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(OCc4ccccc4)cc3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
2-(2-Hydroxyethyl)-4-methoxy-3-pentyloxy-N-[2-(4-benzyloxyphenyl)-ethyl]benzamide (1.33 g, 2.7 mmol, 1.0 eq) was dissolved in DMSO (26 ml), and triethylamine (3.49 ml, 24.3 mmol, 9 eq) and sulfur trioxide-pyridine complex (1.29 g, 8.1 mmol, 3 eq) were successively added under ice-cooling. The mixture was stirred at room temperature for 2 hours. 3N Hydrochloric acid (35 ml) was added to this reaction mixture. The mixture was stirred at room temperature for 30 minutes and e xacted twice with ethyl acetate (40 ml). The organic layers were combined, washed with a saturated aqueous sodium carbonate solution (40 ml) and saturated brine (100 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=2/1) to give 2-[2-(4-benzyloxyphenyl)ethyl]-6-methoxy-5-pentyloxy-2H-isoquinolin-1-one (1.275 g, 100%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[CH2:1]([O:3][C:4]1[C:5]([OH:11])=[CH:6][C:7]([F:10])=[C:8]([CH:9]=1)[CH:24]=[O:25])[CH3:2]
Reactant: CCOc1ccc(F)cc1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CCOc1cc(C=O)c(F)cc1O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The 2-ethoxy-5-fluoro-phenol (14.3 g) described in example 1.2 was dissolved in trifluoroacetic acid (90 ml). This solution was slowly added to a solution of hexamethylene tetramine (25.7 g) in trifluoroacetic acid (90 ml) at 80° C. The mixture was stirred for 1 h at 80° C. and concentrated. Water (250 ml) was added and stirred for 10 min. The mixture was neutralized with Na2CO3 and extracted with ether. The crude product was purified by column chromatography (n-hexane/ethyl acetate) to yield 9.43 g of 5-ethoxy-2-fluoro-4-hydroxy-benzaldehyde as a yellow solid. MS: 184 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](Cl)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.CCN(CC)CC.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a mixture of 10.0 g (37.9 mmol) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.0 mL of Et3N in 200 mL of dry THF at room temperature and under a nitrogen atmosphere was added 33.0 g of piperazine. The mixture was stirred at room temperature for 22.5 hours and then refluxed for 5.5 hours. It was then cooled to room temperature, poured into 250 mL of 5% aqueous NaOH, and extracted with CH2Cl2 (3×). The combined organic portions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (2→5% MeOH saturated with ammonia in CH2 Cl2) to yield the title compound as a glass.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH:11]O>C(O)(=O)C>[CH2:1]([S:5]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCSc1nc[nH]n1
Solvent: CC(=O)O
Product: CCCCS(=O)c1nc[nH]n1
Reaction time: 24 h

Procedure:
To a solution of 15.7 g. 3-butylthio-1,2,4-triazole in 60 ml. glacial acetic acid was added 100 vol. hydrogen peroxide solution (11.4 ml., 1 molecular proportion). The reaction mixture was cooled occasionally during 1 hour to maintain the reaction temperature at 25° - 30°C., and then kept at room temperature for 24 hours. The resulting solution was distilled under reduced pressure to produce a solid residue which was recrystallized from ethyl acetate to give 3-n-butylsulphinyl-1,2,4-triazole, m.p. 82° - 83°C.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].B(OB=O)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([O:22][CH3:23])[CH:15]=1.C(OC)(OC)OC.C(N)CCC.Cl>C(OCC)(=O)C>[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5])=[C:16]([O:22][CH3:23])[CH:15]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=BOB=O
Solvent: CCOC(C)=O
Solvent: CCCCN
Solvent: COC(OC)OC
Product: COc1cc(O)ccc1C=CC(=O)CC(C)=O
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
Ethyl acetate (7 mL), 2,4-pentanedione (9.6 mL, 94 mmol) and boron trioxide (5.9 g, 85 mmol) was placed in a 200 mL reaction vessel with a reflux condenser. To the stirring mixture at 85° C. was added dropwise a solution of 4-hydroxy-2-methoxybenzaldehyde (2.16 g, 14.2 mmol) and trimethyl orthoformate (1.6 mL, 14 mmol) in 14 mL of ethyl acetate. After the reaction mixture was stirred for 30 min at 95° C., n-butylamine (7.0 mL, 71 mmol) was added dropwise with additional stirring for 2 h. The reaction mixture was cooled to 50° C. before addition of 3N HCl (33 mL). After being stirred at 50° C. for 30 min, the mixture was filtered to remove solids. The filtrate was diluted with ethyl acetate, washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 75/25) followed by recrystallization (hexane/ethyl acetate) to obtain the title compound as a pale yellow crystal (1.07 g, 33%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:13]([CH2:14][N:15]([C@@H:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:38]1[O:39][C:40]2[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][C:41]=2[N:42]=1.O>CS(C)=O>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:13]1[CH2:12][CH2:11][N:10]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][C:41]=3[N:42]=2)[CH2:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2oc(Cl)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2oc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.9 %

Procedure:
To a solution of 185 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2.00 mL of DMSO was added 18 mg of sodium hydride (55% dispersion) at room temperature, followed by stirring for 10 minutes. 89 mg of methyl 2-chloro-1,3-benzoxazole-5-carboxylate was added thereto, followed by stirring at 100° C. overnight. 55 mg of methyl 2-chloro-1,3-benzoxazole-5-carboxylate was further added thereto, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate and chloroform-methanol) to obtain 33 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylate as a colorless resinous compound. ESI+: 638
Reaction SMILES: [Si](OCC[N:11]1[C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-])=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28])(C(C)(C)C)(C)C.[NH4+:29].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:27]([O:26][CH2:25][C:12]1[NH:11][C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:29])[C:14]=2[N:13]=1)[CH3:28]
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1CCO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3cccnc3c2[nH]1
Reaction time: 1.5 h

Procedure:
1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide (2.40 g, 5.97 mmol) was dissolved in 60 mL of CH2Cl2 and treated with 6 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (1.19 g, 6.27 mmol) was carefully added. Rapid stirring was continued for 1.5 hours. The reaction mixture was then treated with 50 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 2% Na2CO3 solution (2×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10-15% CMA/CHCl3) gave 1-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.93 g) as a light-brown foam.