Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:12][C:13]([Cl:30])([Cl:29])[C:14]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=2)[CH2:17]1)=[O:15]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:30][C:13]([Cl:12])([Cl:29])[C:14]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:25]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)(=[O:27])=[O:26])[CH:22]=2)[CH2:17]1)=[O:15]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)cc2C1)C(Cl)(Cl)Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 70.7 %

Procedure:
To a solution of 4-trifluoromethyl aniline (213 μL, 1.70 mmol) in pyridine (270 μL) was added 2-(trichloroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride (617 mg, 1.70 mmol) at room temperature, and the mixture was stirred at 60° C. for 1.5 hr. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with 1 mol/L hydrochloric acid, brine and water. The organic layer was dried over anhydrous sodium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to afford the title compound as a colorless powder (586 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl([O-])(=O)(=O)=O.CN([P+](N(C)C)(N(C)C)Cl)C.C(N(CC)C(C)C)(C)C.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]([C:49]1[S:50][CH:51]=[C:52]([C:54]2[O:55][C:56]3[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=3[CH:58]=2)[N:53]=1)[C:42]([C:44]1[S:45][CH:46]=[CH:47][CH:48]=1)=[O:43]>CN1C(=O)CCC1>[O:55]1[C:56]2[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=2[CH:58]=[C:54]1[C:52]1[N:53]=[C:49]([N:41]([CH2:40][CH2:39][CH2:38][NH:37][C:9](=[O:11])[CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:42]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)=[O:43])[S:50][CH:51]=1
Reactant: NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)[P+](Cl)(N(C)C)N(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCCCC1)NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of 1-piperidinepropionic acid (3 mg, 0.02 mmol) and tris(dimethylamino)chlorophosphonium perchlorate (7 mg, 0.02 mmol) was dissolved in NMP (200 μL) followed by the addition of N,N-diisopropylethylamine (17 μL, 0.1 mmol). The reaction mixture was maintained at room temperature for 20 min, then N-(3-aminopropyl)-N-(4-(benzofuran-2-yl)thiazol-2-yl)thiophene-2-carboxamide (7.7 mg, 0.02 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The resulting mixture was subjected to HPLC purification (Method Z) to provide the title compound (3.2 mg) as a pale yellow solid. LC/MS (ESI) m/z 523.5 [M+H]. HPLC retention time (Method C)=3.15 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[O:18][CH2:19][C:20](=[O:27])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][N:35]=2)[C:30]([CH:37]=O)=[CH:29]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:28]1[C:36]2=[N:35][CH:34]=[CH:33][CH:32]=[C:31]2[C:30]([CH:37]=[C:19]2[O:18][C:17]([NH:16][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[CH:7][C:2]=3[CH3:1])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]2=[O:27])=[CH:29]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OCc3cccnc3)cc2C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCc3cccnc3)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.1 %

Procedure:
To a solution of ethyl 2-{[2-methyl-4-(3-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.032 g, 0.20 mmol) in ethanol (5.0 mL), L-proline (0.0050 g, 0.043 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[S:10])[NH2:9])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Ca+2].Br[CH:17]1[C:22](=O)[CH2:21][CH2:20][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18]1>CC(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[S:10][C:17]3[CH2:18][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21][C:22]=3[N:9]=2)=[CH:3][CH:2]=1
Reactant: NC(=S)Cc1ccncc1
Reactant: CCOC(=O)N1CCC(=O)C(Br)C1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Product: CCOC(=O)N1CCc2nc(Cc3ccncc3)sc2C1
Temperature: 25 °C
Yield: 70 %

Procedure:
2-(Pyridin-4-yl)ethanethioamide (6 mmol) and 20 mmol of calcium carbonate were added to a solution of ethyl 3-bromo-4-oxopiperidine-1-carboxylate (1 g; 4 mmol; cf. AMN-01) in 20 ml of 2-propanol. The reaction mixture obtained was heated under reflux for 20 hours. The course of the reaction was monitored by thin layer chromatography. The reaction mixture was then cooled to 25° C. and filtered over Celite. The filter cake was washed several times with ethyl acetate. The organic phase was concentrated under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed successively with water and saturated sodium chloride solution. After the organic phase had been dried over sodium sulfate, the solvent was removed under reduced pressure. The crude product obtained was purified by column chromatography (30% ethyl acetate in hexane). The desired product was obtained in a yield of 70%.
Reaction SMILES: [CH:1]1[C:6]([N:7]=[C:8]=[S:9])=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].[NH2:29][C:30]1[C:39]2[N:40]=[C:41]([CH2:46][CH2:47][CH2:48][CH3:49])[N:42]([CH2:43][CH2:44][NH2:45])[C:38]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]=1.O>N1C=CC=CC=1>[NH2:29][C:30]1[C:39]2[N:40]=[C:41]([CH2:46][CH2:47][CH2:48][CH3:49])[N:42]([CH2:43][CH2:44][NH:45][C:8]([NH:7][C:6]3[CH:1]=[CH:2][C:3]([C:13]4[C:14]5[C:15]([O:21][C:22]6[C:23]=4[CH:24]=[CH:25][C:26](=[O:28])[CH:27]=6)=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=5)=[C:4]([CH:5]=3)[C:10]([OH:12])=[O:11])=[S:9])[C:38]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNC(=S)Nc1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Yield: 56.5 %

Procedure:
A solution of fluorescein-5-isothiocyanate (778 mg, 2.0 mmol) in pyridine (5 mL) was added to a solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine (566 mg, 2.0 mmol) in pyridine (5 mL). The reaction mixture was heated at reflux for 30 minutes and then poured into water (50 mL). The resulting orange solid was isolated by filtration, dried under high vacuum and then recrystallized from pyridine to provide 0.76 g of the desired product as an orange solid, m.p. >245°. Analysis by high performance liquid chromatography indicated pure product. Analysis: Calculated for C37H32N6O5S: % C, 66.06; % H, 4.79; % N, 12.49; Found: % C, 63.03; % H, 4.89; % N, 12.59. High resolution mass spectroscopy: TM=673.2233 Da., MM=673.2251 Da.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]Br.O>N1C=CC=CC=1>[Br:9][C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1
Reactant: BrBr
Reactant: Cc1ccc(O)cn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(O)c(Br)n1
Reaction time: 1.5 h

Procedure:
To a solution of 5-hydroxy-2-methylpyridine (Commercial, Aldrich, 44.5 g) in pyridine (400 ml) is added dropwise over 30 min at room temperature a solution of bromine (71.64 g) in pyridine (550 ml). The reaction mixture was stirred for an additional 1.5 h. The reaction mixture was poured into water (4 liters), stirred for a few minutes and extracted with diethyl ether (4×300 ml). The combined organics were dried over sodium sulphate and concentrated in vacuo to give a brown solid that was purified through silica using a 0-30% ethyl acetate in hexane system, to give the title compound as a beige solid, 37 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28].O>C(Cl)(Cl)Cl>[F:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FCCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.1 %

Procedure:
673 mg (corresponding to 2.0 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 25 mL of N,N-dimethylformamide, and 831 mg (corresponding to 6.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 275 μL (corresponding to 3.0 mmol) of 1-bromo-3-fluoropropane, and then stirred at room temperature for 24 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform), and further by recycle preparative HPLC(HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 349 mg (corresponding to 0.881 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 1-5, Step 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[CH:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:9][S:10]2)=[CH:5][CH:4]=1.O1CCC[CH2:23]1.C([N-]C(C)C)(C)C.[Li+].CI>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)([CH3:23])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Reaction time: 0.75 h
Yield: 72 %

Procedure:
To 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (725 mg, 2.41 mmol) obtained in Example 25 was added dry tetrahydrofuran (30 ml). Then lithium diisopropylamide (2.41 ml, 4.83 mmol, 2.0 mol hexane/tetrahydrofuran solution) was added dropwise thereto at -78° C. The reaction mixture was stirred for 45 minutes and methyl iodide (7.5 ml, 120.6 mmol) was added thereto. The reaction solution was stirred for one hour at -78° C. and for 24 hours at -10° C. and, after adding water, extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=9:1) to obtain 550 mg (yield: 72%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (261 mg, 0.83 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (214 mg, 0.83 mmol), EDC(hydrochloride) (239 mg, 1.25 mmol), HOBt (168 mg, 1.24 mmol), and DMAP (20 mg, 0.16 mmol) in DMF (8 mL) was stirred at room temp for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 470 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]amino]-1propoxy]benzoate as a pale yellow amorphous solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: OC1CCNCC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCC(O)CC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxypiperidine (0.198 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH-CHCl3) to afford the title compound E24 as an off-white solid (0.20 g, 58%). mp 142-144° C.; HPLC: Hichrom RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 5.5); solvent B=CH3CN], Gradient elution program: T/%B=0/20, 10/20,25/80, 40/80, 55/60, 65/20, 70/20; 270 nm, Rt 40.56 min, 98.60% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([CH2:20][C:21]([OH:23])=[O:22])=[C:12]2[CH3:24])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:25]#[N:26].[CH3:27]OC(=O)CC1C2C(=NC=CC=2)NC=1CC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([CH2:20][C:21]([OH:23])=[O:22])=[C:12]2[CH2:24][CH3:27])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:25]#[N:26]
Reactant: CCc1[nH]c2ncccc2c1CC(=O)OC
Reactant: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(C#N)c1
Product: CCc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(C#N)c1

Procedure:
The titled compound is prepared analogously to [1-(4-chloro-3-cyano-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (Example 103) by replacing (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester with (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (Intermediate 87c). (MH+ 404)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: CCCCOC(=O)Cl
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended 60% sodium hydride (60 mg). The compound 1 (200 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, n-butyl chloroformate (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-n-butoxycarbonyl-quinoline (compound 9, 142 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][OH:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O.O>ClCCl>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][OH:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[O:21][Si:28]([CH3:31])([CH3:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CO)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC1(CO)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of 0.59 g of 4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 48 and 1.17 ml of 2,6-luthidine in 5 ml of dichloromethane was cooled to 0° C. under nitrogen, combined with 1.25 ml of trimethylsilyl trifluoromethanesulfonate and stirred. After 30 minutes, the reaction solution was poured into water and extracted with ether, and the combined organic layers were concentrated. The residue was dissolved in 10 ml of THF, 5% hydrochloric acid was added and the solution was stirred for 1 hour, after which the reaction solution was concentrated and extracted with water and ether. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 9% ethyl acetate to give 0.62 g of 4,6-di-t-butyl-2-hydroxymethyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran as a colorless oil (yield 84%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1.[C:13]([C:15](=[C:21](OCC)[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C(O)C.Cl>O>[NH2:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][N:7]=2)[N:10]=[C:21]([CH3:22])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: NNc1ccc(C(F)(F)F)cn1
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc(C(F)(F)F)cn2)c1N
Yield: 54.3 %

Procedure:
5-(Trifluoromethyl)pyridin-2-ylhydrazine (10.0 g) described in Reference Example 8 and ethyl 2-cyano-3-ethoxy-3-methylacrylate (10.3 g) were added to a mixed solvent of ethanol (40 ml) and 1N hydrochloric acid aqueous solution (40 ml), and the mixture was stirred at reflux temperature for three hours. Water was added to the reaction solution to give ethyl 5-amino-3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylate (9.6 g). Next, the compound was added to tetrahydrofuran (50 ml), isoamyl nitrite (20 g) was added and the mixture was stirred at reflux temperature for five hours. The reaction solution was concentrated, a mixed solvent of ethanol (40 ml) and water (40 ml) and sodium hydroxide (5 g) were added and the mixture was stirred at reflux temperature for two hours. Ethanol was evaporated, diluted hydrochloric acid was added and the precipitated solid was recrystallized from aqueous methanol to give the titled compound.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[OH:22][CH2:23][CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[O:22][CH2:23][CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=1
Reactant: COc1ccccc1CNc1ccc2c(I)cccc2n1
Reactant: OCCSc1ccccc1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1ccc2c(OCCSc3ccccc3)cccc2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
(5-Iodo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (0.4 g, 1 mMol) and 2-hydroxyethyl-phenylsulfide (0.32 g, 2 mMol) were heated in toluene together with CuI (10 Mol-%), phenantroline (20 Mol-%) and CsCO3 (0.67 g, 2 mMol) to 100° C. for 24 h. After cooling to ambient temperature the reaction mixture was extracted twice with toluene, the combined organic phases were extracted with water and subsequently dried with sodium sulfate. After evaporation the residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 100:0->60:40 gradient) to yield (2-methoxy-benzyl)-[5-(2-phenylsulfanyl-ethoxy)-quinolin-2-yl]-amine (0.4 g, 93%) as a yellow oil,
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13]=[O:14])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C.CC1C2C=[C:22]3[O:25][CH2:26]C(=O)CO[C:21]3=CC=2CC1>>[CH3:10][C:8]1([CH3:9])[C:3]2[CH:2]=[C:1]3[O:11][CH2:12][C:13](=[O:14])[CH2:26][O:25][C:22]3=[CH:21][C:5]=2[CH2:6][CH2:7]1
Reactant: CC1CCc2cc3c(cc21)OCC(=O)CO3
Reactant: CC(C)=CCCC(C)CCOCC=O
Product: CC1(C)CCc2cc3c(cc21)OCC(=O)CO3

Procedure:
Odor: Marine-aldehyde-like, floral-rosy odor with nuances of citronelloxyacetaldehyde [(3,7-dimethyl-6-octenyl)oxyacetaldehyde]. -IR (film): ν=1322/1253/1281/1350 cm−1 (ν ring), 1040/1067 cm−1 (ν C—O—C), 1484/1438 cm−1 (ν C═C, Ar), 1736 cm−1 (ν C═O). 1H-NMR (CDCl3): δ=1.22 (s, 6H, 1-Me2), 1.92 (t, J=7.2 Hz, 2H, 2-H2), 2.79 (t, J=7.2 Hz, 2H, 3-H2), 4.67 (d, J=2.8 Hz, 4H, 6-, 8-H2), 6.75 (s, 1H, 4-H), 6.81 (s, 1H, 10-H). -13C-NMR (CDCl3): δ=28.43 (2q, 1-Me2), 29.29 (t, C-3), 41.68 (t, C-2), 43.61 (s, C-1), 75.47/75.51 (2t, C-6,-8), 113.99 (d, C-10), 116.31 (d, C-4), 138.98 (s, C-3a), 146.83/147.22 (2s, C-4a, -9a), 148.30 (s, C-10a), 205.06 (s, C-7). -MS (EI): m/z (%)=133 (33) [C9H9O+], 145 (6) [C11H13+], 161 (7) [M+-CH3-2CO], 189 (2) [M+-CH3—CO], 217 (100) [M+-CH3], 232 (30) [M+].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Yield: 23.4 %

Procedure:
A mixture of 4-fluorobenzonitrile (3.6 g) and N-tert-butyloxycarbonylpiperazine (5.58 g) in acetonitrile (60 mL) was heated at 80° C. for 72 hours. The reaction mixture was then cooled to room temperature and then treated with a mixture of sodium bicarbonate solution and ethyl acetate (300 mL, 1:1, v/v). The organic phase was separated and then evaporated. The residue was subjected to chromatography on silica gel eluting with a mixtures of heptane and ethyl acetate (from 3:7 to 1:1, v/v) to give the title compound (2 g) as a white solid.