Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].C(#N)C.[C:50](=[O:53])(O)[O-].[Na+].[CH3:55][O:56][C:57]1[CH:65]=[CH:64][C:60]([C:61](Cl)=[O:62])=[C:59](OC)[C:58]=1[O:68][CH3:69]>O>[CH3:69][O:68][C:58]1[CH:59]=[C:60]([CH:64]=[C:65]([O:53][CH3:50])[C:57]=1[O:56][CH3:55])[C:61]([N:41]1[CH2:42][CH2:43][C:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][OH:46])[CH2:40]1)=[O:62]
Reactant: O=C([O-])O
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1OC
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (+)-3-(3,4-dichloro-phenyl)-3-(2-hydroxyethyl)-pyrrolidine (R, R)-di-p-anisoyltartaric acid salt (0.14 g, 0.21 mmol) ethyl acetate (15 mL, acetonitrile (6 mL), water, (6 mL) and sodium bicarbonate (0.09 g, 1.03 mmol). Cool to 0° C. in an ice-salt bath. Add trimethoxybenzoyl chloride (0.048 g, 0.21 mmol). After 30 minutes, warm to ambient temperature. After 30 minutes at ambient temperature, partition the reaction mixture between ethyl acetate and saturated aqueous sodium chloride solution. Extract the organic layer with 1M hydrochloric acid solution, then saturated aqueous sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.11 (silica gel, ethyl acetate).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>CC(O)(C)C>[CH2:16]([O:15][C:7]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1C=CCC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C(=O)OCC)[C@@H]1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
Under an atmosphere of argon, 12.6 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Tsdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 152 μL (1.0 mol) of diethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 233 mg (96% yield) of the title compound. After this was converted into an ethylene ketal derivative by the same procedure as in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 96% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])OCC(Cl)(Cl)Cl)=[CH:5][CH:4]=1.[C:18]1([C:24]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:26][N:25]=[C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:28]=3)[CH2:30][CH2:31]2)=[O:17])=[CH:5][CH:4]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1

Procedure:
A solution of 2,2,2-trichloroethyl (6-methoxypyridin-3-yl)carbamate (300 mg, 1.00 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol), diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 5 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (84.0 mg, 21.2%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH:11](N(CC)C(C)C)(C)[CH3:12].COCCl>O1CCCC1.ClCCl>[CH3:11][CH2:12][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: CCN(C(C)C)C(C)C
Agent: COCCl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.4 %

Procedure:
A solution of 2.0 g (14.0 mmol) of methyl 3-hydroxy-5-isoxazole carboxylate and 29.2 ml (16.8 mmol) of N,N-diisopropylethylamine in 20 ml of tetrahydrofuran was treated with 1.27 ml of chloromethyl methyl ether. After being stirred at ambient temperature for 2 h, the solution was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 10% methanol in dichloromethane provided 129.6 mg (78%) of the desired compound as a white solid. 1H NMR (CDCl3) δ3.57 (s, 3H), 3.96 (s, 3H), 5.37 (s, 2H), 6.64 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:27])[CH2:10][C@H:11]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:28]1[C:23]([C:22]2[CH:21]=[CH:20][C:19]([C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:4]3[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)=[O:27])=[CH:26][CH:25]=2)=[N:24][N:30]=[N:29]1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2nnn[nH]2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 37.3 %

Procedure:
To a solution of (R)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolyl-propyl)benzonitrile (60 mg, 168 μmol) in N,N-dimethylformamide (1 mL) was added sodium azide (54.7 mg, 842 μmol) and ammonium chloride (45.0 mg, 842 μmol). The reaction mixture was heated to 80° C. for 24 h, then another portion of sodium azide (54.7 mg, 842 μmol) and ammonium chloride (45.0 mg, 842 μmol) was added and the reaction mixture was stirred at 80° C. for another 72 h, then concentrated in vacuo. The residue was suspended in dichloro-methane/methanol 19:1, filtered, and the filtrate was purified by chromatography (SiO2, gradient dichloromethane to dichloromethane/methanol 9:1) afforded the product as a salt. This was partitioned between ethyl acetate and 1 M aq. hydrochloric acid solution. After removal of the aqueous layer, the organic layer was dried over magnesium sulfate, filtered, evaporated and precipitated with dichloromethane and heptane to produce the title compound (25 mg, 37%). White solid, MS (ESI+): m/z=: 400.2 [M+H]+.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[CH3:13][S:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[NH2:33])(=[O:16])=[O:15].Cl.N1C=CC=CC=1>C(#N)C>[CH2:2]([C:3]1[N:22]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:1]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reaction time: 0.67 h
Yield: 92.1 %

Procedure:
Triethyl orthopropionate (2.5 mL, 12 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.2 g, 10 mmol) in acetonitrile (50 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 40 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide 3.2 g of 2-ethyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as an oil which slowly solidified.
Reaction SMILES: [C:1](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(NCC4C=CC=CC=4)=CN=C3CC2)=O)=CC=1)=N)(C)([CH3:3])[CH3:2].[CH2:39]([O:46][C:47](=[O:87])[N:48]([CH2:84][CH:85]=[CH2:86])[C:49]1[C:54](=[O:55])[N:53]2[C@H:56]([C:61](=[O:83])[NH:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([NH:72][C:73]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)=[O:74])=[NH:71])=[CH:66][CH:65]=3)[CH2:57][C@:58]([NH2:60])([CH3:59])[C:52]2=[N:51][CH:50]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CC(C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:39]([O:46][C:47](=[O:87])[N:48]([CH2:84][CH:85]=[CH2:86])[C:49]1[C:54](=[O:55])[N:53]2[C@H:56]([C:61](=[O:83])[NH:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([NH:72][C:73]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)=[O:74])=[NH:71])=[CH:66][CH:65]=3)[CH2:57][C@:58]([NH:60][CH:1]([CH3:3])[CH3:2])([CH3:59])[C:52]2=[N:51][CH:50]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)NC(C)C
Yield: 28.1 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, 26a (30 mg, 0.045 mmol), acetone (5.3 mg, 0.090 mmol) and NaBH(OAc)3 (26.8 mg, 0.127 mmol) yielded 8.9 mg (28.1%) of 27a. MS (ESI) 706.2 (M+H+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:15]([NH:17][C:18]([NH:20][C:21]1[N:39]=[C:24]2[CH:25]=[C:26]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:27]=[C:28]([C:29]([NH:31][NH2:32])=[O:30])[N:23]2[N:22]=1)=[O:19])[CH3:16]>O1CCOCC1>[C:1]([NH:32][NH:31][C:29]([C:28]1[N:23]2[N:22]=[C:21]([NH:20][C:18]([NH:17][CH2:15][CH3:16])=[O:19])[N:39]=[C:24]2[CH:25]=[C:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:27]=1)=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NN)n2n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NNC(C)=O)n2n1

Procedure:
Acetic anhydride (0.95 mL, 10 mmol), triethylamine (1.2 mL, 8.6 mmol) and the product of Step 1 (0.996 g, 2.93 mmol) in dioxane (100 mL) was refluxed for 6 h. The solution was cooled and the product was filtered, washed with water and then dried to give 1-[5-(N′-acetyl-hydrazinocarbonyl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-ethyl-urea as a solid ACPI-MS Found: [M+H]+=383.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[N:7]=[C:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:9][C:10]=1[C:11](OCC)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[N:7]=[C:8]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:9][C:10]=1[CH2:11][OH:12]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of ethyl 4-(3,4-dichlorobenzyl)-2-morpholinothiazole-5-carboxylate (4.92 g, 12.2 mmol) in THF (100 mL) was added a 2.00 M solution of LAH in THF (12.9 mL, 25.8 mmol) and the resulting solution was stirred for 2 hours at room temperature. The reaction was quenched by adding saturated NH4Cl (26 mL) followed by 1M HCl (26 mL). Water (100 mL) and ethyl acetate (200 mL) were then added. The layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→100/0) to give 2.87 g (65% yield) of the title compound. as a white solid. LC/MS (FA) ES+ 359, 361. 1H NMR (400 MHz, CDCl3) δ: 7.34-7.31 (m, 2H), 7.09 (dd, 1H, J=6.0, 2.0 Hz), 4.66 (d, 2H, J=1.2 Hz), 3.84 (s, 2H), 3.79-3.77 (m, 4H), 3.42-3.39 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]([CH2:10][CH3:11])([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1.C(N(CC)CC)C>ClCCl.O>[CH2:1]([C:3]1([CH2:10][CH3:11])[C:7](=[O:8])[NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[NH:21][C:4]1=[O:5])[CH3:2]
Reactant: COc1ccc(N)c(N)c1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(CC)C(=O)Nc2ccc(OC)cc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
Diethylmalonyl dichloride (0.95 ml, 5.5 mmol) was added to a dichloromethane solution (20 ml) of 4-methoxy-o-phenylenediamine (691 mg, 5 mmol) and triethylamine (1.7 ml, 12.5 mmol) at 0° C., and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1→1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 452.3 mg (yield: 34%) of 3,3-diethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: C1CCNC1
Product: COc1cccc2cc(C(=O)N3CCCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and pyrrolidine to give 2-Pyrrolidinylcarbonyl-7-methoxybenzofuran (Compound 309a). Successively, it was formylated to give 2-pyrrolidinyl-carbonyl-4-formyl-7-methoxybenzofuran (Compound 309b), then compound 309b was reacted with methylamine hydrochloride to give compound 309 as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1
Reactant: c1ccc(-c2cc[nH]n2)nc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Compound 17a (1 g, 6.9 mmol) obtained from the aforesaid process and 3,4-difluoro-nitrobenzene (0.74 mL) were dissolved in N,N-dimethylformamide (20 mL), and then anhydrous potassium carbonate (1.9 g) was added thereto. The mixture was reacted at 100° C. for 4 hours. After completion of the reaction, the reactant mixture was cooled to room temperature. Water was added to the mixture, resulting in a substantial amount of precipitate. Then, the precipitate was suction-filtered, and the filter cake was recrystallized with acetone to get the product 18a as a white powder (1.7 g), with a yield of 93.4%.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].C(Cl)(C([Cl:24])=O)=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([Cl:24])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sc2ccc(-c3ccccc3)cc2c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 13d (136.2 mg, 0.5 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.064 mL, 0.75 mmol), followed by DMF (0.01 mL, 0.125 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 13e as a light pink powder, which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]([CH2:34][CH2:35][CH3:36])[C:14]3[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]([CH2:34][CH2:35][CH3:36])[C:14]3[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN(Cc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCN(Cc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To a mixture of methyl 3-[4-({4-[[(4-phenyl-1,3-thiazol-2-yl)methyl](propyl)amino]benzyl}oxy)phenyl]propanoate (240 mg, 0.48 mmol), ethanol (5 mL) and tetrahydrofuran (5 mL) was added 2N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4-4:1 in volume ratio) to give the title compound (75 mg, yield 32%) as colorless prism crystals (recrystallized from acetone-heptane).
Reaction SMILES: S(Cl)([Cl:3])=O.C(O)(=O)C(O)=O.O[CH2:12][C@@H:13]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14]1.O>C(Cl)(Cl)Cl>[Cl:3][CH2:12][C@@H:13]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14]1
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CO)c2c1
Reactant: O=S(Cl)Cl
Agent: O=C(O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CCl)c2c1
Temperature: 60 °C

Procedure:
3.6 cm3 of thionyl chloride were added dropwise, at a temperature in the region of 20° C., to a stirred solution of 2.9 g of (3R,4R)-3-hydroxymethyl4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine oxalate in 20 cm3 of chloroform. The mixture was heated for 2 hours at a temperature in the region of 60° C. and then, after cooling, was poured onto 50 cm3 of water to which 250 g of ice had been added. After separating by settling from the chloroform phase, the mixture was extracted with 100 cm3 of dichloromethane. 5 g of sodium hydrogencarbonate were added to the aqueous phase, which was then extracted with 2 times 200 cm3 of dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40°. 1.3 g of (3R,4R)-3-chloromethyl-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine were obtained in the form of an oil with a brown color.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][NH:24][C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O.Cl.[NH2:42][CH:43]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45]>O1CCOCC1.C(N(CC)CC)C>[CH2:16]([O:23][NH:24][C@H:25]([C:30]([NH:42][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[O:32])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)C[C@H](NOCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)[C@H](CC(C)C)NOCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
22.90 g of dicyclohexylcarbodiimide was added to 300 ml of a solution of 26.39 g of N-benzyloxyleucine and 13.35 g of N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove the insoluble materials, whereby a colorless solution was obtained. Separately, 20 ml of triethylamine was added to 300 ml of a suspension of 28.57 g of diethyl aminomalonate hydrochloride in anhydrous dioxane. To the mixture was applied an ultrasonic wave for 1 hour. Thereto was added the above colorless solution. The mixture was stirred at room temperature for 16 hours and then at a bath temperature of 100° C. for 3.5 hours. The reaction mixture was subjected to distillation to remove the solvent. The residue was dissolved in 1,000 ml of ethyl acetate. The solution was washed with 1N hydrochloric acid, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride in this order, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent to obtain 39.22 g of diethyl N-(N-benzyloxyleucyl)aminomalonate as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:18]1[C:14]2=[N:15][C:16]([CH3:17])=[C:11]([CH:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:7]([OH:9])=[O:8])[C:12]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[O:27][CH2:26][CH2:25][CH2:24]4)=[C:13]2[CH:20]=[CH:19]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: BrCc1ccccc1
Product: Cc1nc2c(ccn2Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.43 (m, 1 H), 7.39-7.28 (m, 5 H), 7.24-7.17 (m, 1 H), 7.06 (t, J=3.3 Hz, 1 H), 6.94 (dd, J=6.0, 8.2 Hz, 1 H), 6.29 (dd, J=3.4, 11.6 Hz, 1 H), 5.66-5.48 (m, 3 H), 4.32-4.23 (m, 2 H), 2.97-2.81 (m, 2 H), 2.79 (s, 3 H), 2.15-2.06 (m, 2 H), 0.97 (s, 9 H); LC/MS (m/z) ES+=485.37 (M+1).