Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([C:20]2[N:21]=[N:22][N:23]([CH2:25][C:26](OC)=[O:27])[N:24]=2)[CH:17]=[C:16]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.CC(O)C.CCCCCC>[CH3:1][C:2]1[CH:19]=[C:18]([C:20]2[N:21]=[N:22][N:23]([CH2:25][CH2:26][OH:27])[N:24]=2)[CH:17]=[C:16]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1
Reactant: COC(=O)Cn1nnc(-c2cc(C)c(OCCCCCc3cc(C)no3)c(C)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCCCCOc2c(C)cc(-c3nnn(CCO)n3)cc2C)on1
Yield: 88 %

Procedure:
A solution of 8.0 g 5-{5-[2,6-dimethyl-4- (2-methoxycarbonylmethyl-2H-tetrazol-5-yl)phenoxy]pentyl}-3-methylisoxazole (Example 52) in 50 ml tetrahydrofuran was added dropwise to a stirred suspension of 0.53 g lithium aluminum hydride in 250 ml dry tetrahydrofuran under nitrogen with cooling in an ice bath. The reaction mixture was allowed to come to room temperature and then treated with water and 15% sodium hydroxide. Isolation of the product provided 6.56 g (88%) of 5-{5-[2,6-dimethyl-4-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]phenoxy]pentyl}-3-methylisoxazole, m.p. 69-70° C. (from 2-propanol/hexane).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH:23]([C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=1[Cl:32])[OH:24].O>CN(C)C=O>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH:23]([C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=1[Cl:32])[O:24][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothiene-2-yl(5-bromo-2-chlorophenyl) methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothiene-2-yl(5-bromo-2-chlorophenyl) methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothiene-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:6])=[O:4]>[Pt]=O.C(O)C>[NH2:14][C:13]1[C:8]([O:7][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH3:6])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C(C)Oc1ncccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)C(C)Oc1ncccc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
A mixture of 1.7 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine, 102 mg of platinum oxide, and 7.5 ml of ethanol was stirred at room temperature under an atmosphere of hydrogen gas for 3.5 hours. The gas in the atmosphere on the reaction system was replaced with nitrogen gas, and the reaction mixture was filtered through Celite. The filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 1.16 g of 3-amino-2-{1-(methoxycarbonyl)ethoxy}pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([NH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=[CH:13][C:14]=1[CH2:15][OH:16].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[C:15]=[O:16])[CH:13]=[CH:12][C:11]([NH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:10]1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(CO)c(-c2ccc(Cl)cc2Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNC1=CC(c2ccc(Cl)cc2Cl)C(=C=O)C=C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Using the method of Swern, et al., N-(2-{[3-(2,4-dichlorophenyl)-4-(hydroxymethyl)phenyl]amino}ethyl)(tert-butoxy)carboxamide (100 mg) is dissolved in anhydrous methylene chloride (1 ml) and added to a premixed solution of oxalyl chloride (1.5 eq) and DMSO (3 eq) in methylene chloride (25 ml) which has been stirring at −78° C. for 15 min. The resulting solution is stirred at −78° C. for an additional 30 min, at which time triethyl amine (6 eq) is added. The resulting suspension is allowed to warm to room temperature. After 15 min., water (1 ml) is added and the layers separated. The aqueous layer is extracted with methylene chloride (2×10 ml), and the combined organic layers dried (sodium sulfate) and concentrated to afford aldehyde 8 in 70–80% yield as a light yellow foam. This product proves to be unstable and is used without further manipulation.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:15][C:16]1[N:17]=[C:18]([O:3][CH2:4][CH2:5][O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: Brc1cccc(Br)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCOc2cccc(Br)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a 60% suspension of sodium hydride (0.22 g) in DMF (30 mL), 4-(2-hydroxyethoxy)benzaldehyde (1.00 g) was added at 0° C., and the suspension was stirred for 30 minutes. Subsequently, 2,6-dibromopyridine (2.14 g) and tetrabutylammonium iodide (0.022 g) were sequentially added to the mixture at 0° C., and the resultant mixture was stirred at room temperature for two hours. After completion of reaction, the reaction mixture was poured into an ice-water mixture, and the thus-formed organic matter was separated through extraction by use of ethyl acetate, followed by washing with water. The washed product was dried over magnesium sulfate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was purified by means of a silica gel column, to thereby yield 1.50 g of the title compound as colorless crystals (yield 77.3%).
Reaction SMILES: C(OCCCC)CCC.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[CH3:22][C:23]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:27][CH:26]=[CH:25][N:24]=1>O>[CH3:22][C:23]1[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:27][CH:26]=[C:25]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:24]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1nccnc1-c1ccccc1
Solvent: CCCCOCCCC
Solvent: O
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)cnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
In a nitrogen atmosphere, 10 mL of a dibutyl ether solution containing phenyl lithium (produced by Wako Pure Chemical Industries, Ltd., 2.1 mol/L) and 120 mL of diethylether were mixed. While the mixed solution was being cooled with ice, 2.87 g of 2-methyl-3-phenylpyrazine was added thereto and stirred at a room temperature for 24 hours. Water was added into this mixture, and an organic layer was extracted with ethyl acetate. The organic layer obtained was dried with magnesium sulfate. The solution after drying was added with activated manganese dioxide excessively and filtration was conducted. A solvent of the obtained filtrate was distilled off, so that a residue was obtained. This residue was purified by silica gel column chromatography which uses dichloromethane as a developing solvent; thereby obtaining an objective pyrazine derivative Hmppr-P (orange oily substance, yield of 12%). A synthetic scheme of Step 1 is shown in the following (a-5).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[C:42]1([C:48]2[N:52]=[C:51]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[O:50][N:49]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:56]1[CH2:55][CH2:54][CH:53]([C:51]2[O:50][N:49]=[C:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:52]=2)[CH2:58][CH2:57]1)=[O:8]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: c1ccc(-c2noc(C3CCNCC3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCCC(F)(F)F)N1CCC(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and diisopropylethylamine (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 4-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (8c) (0.85 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Yield 79%; 1H NMR (CDCl3) δ 8.06-8.09 (m, 2H), 7.48-7.51 (m, 3H), 4.49-4.54 (m, 1H), 3.90-3.94 (m, 1H), 3.24-3.33 (m, 2H), 2.97-3.06 (m, 1H), 2.46 (t, J=7.2 Hz, 2H), 2.17-2.24 (m, 4H), 1.93-1.98 (m, 4H). tR LCMS 6.0 min. Purity >99%; MS [M+H]+ m/z 368.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:27])[N:7]([CH2:25][CH3:26])[CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][CH:16]=2)=[O:12])([CH3:4])[CH3:3].[CH2:28](NCCNC(C1NC2C(C=1)=CC([N+]([O-])=O)=CC=2)=O)CC>>[CH3:4][C:2]([O:5][C:6](=[O:27])[N:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][CH:16]=2)=[O:12])[CH2:25][CH2:26][CH3:28])([CH3:1])[CH3:3]
Reactant: CCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Reactant: CCCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: CCCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
A similar procedure as described for preparation of 78 from compound 81 (0.12 g, 0.413 mmol) gave brown powder (0.142 g, 88%). ESI MS: 391.17 (M+H+), 413.15 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: COc1ccc(CCCCO)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCCCOS(C)(=O)=O)c(OC)c1
Yield: 76 %

Procedure:
Ester 77 was prepared by typical procedure E from alcohol 76 (4.15 g, 0.021 mol), methanesulfonyl chloride (2.4 mL, 0.03 mol) and triethylamine (20 mL). Crude 77 (4.6 g, 80%) was isolated as a yellow oil
Reaction SMILES: [CH2:1]([N:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:4]([C:6]1[C:7](=[O:20])[N:8]([CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[C:13]([CH2:17][CH3:18])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[OH-].[Na+].Cl.O.C([O-])(=O)C.[Ca+2:35].C([O-])(=O)C>O>[Ca:35].[CH2:1]([N:3]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:4]([C:6]1[C:7](=[O:20])[N:8]([CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[C:13]([CH2:17][CH3:18])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: CCc1cccc2c1c(O)c(C(=O)N(CC)c1ccccc1)c(=O)n2C
Agent: Cl
Solvent: O
Product: [Ca]
Temperature: 25 °C

Procedure:
N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide (28.5 mmol, 10.0 g) was dissolved in a mixture of water (200 mL) and 10M NaOH (28.5 mmol, 2.85 mL), and pH was adjusted to 7.5-8.0 with 1M HCl. To this solution at 50° C. was added during 15 min a solution of calcium acetate hydrate (15 mmol, 2.67 g) in water (50 ml) and the resultant thick emulsion was allowed to cool to room temperature and the precipitate was filtered and washed with water. The precipitate was dried in vacuum to give 8.96 g of an amorphous calcium salt.
Reaction SMILES: CS([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=O)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][OH:26])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:23][CH2:24][CH2:25][O:26][C:5]2[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]3[N:6]=2)=[CH:21][CH:22]=1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Reactant: OCCSc1ccc(Cl)cc1
Product: Cc1cc(C)n2nc(OCCSc3ccc(Cl)cc3)nc2n1
Yield: 38 %

Procedure:
The title compound was prepared according to the experimentals described for Example 11 above from 2-methanesulfonyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine and 2-[(4-chlorophenyl)sulfanyl]ethan-1-ol in 38% yield. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.47 (dd, 1H), 7.45 (dd, 1H), 7.39 (dd, 1H), 7.37 (dd, 1H), 7.08 (s, 1H), 4.51 (t, 2H), 3.45 (t, 2H), 2.62 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:2].Cl[CH2:17][C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2>>[N:22]12[CH2:23][CH2:24][CH2:25][C:18]1([CH2:17][N:3]([CH:1]=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=1)[CH2:19][CH2:20][CH2:21]2
Reactant: ClCC12CCCN1CCC2
Reactant: O=CNc1cccc(-c2ccccc2)c1
Product: O=CN(CC12CCCN1CCC2)c1cccc(-c2ccccc2)c1

Procedure:
The procedures described in Example 2 were repeated except that 3-formylamino-1,1'-biphenyl (286 mg, 1.45 mmol) and 5-chloromethyl-1-azabicyclo[3.3.0]octane (hydrochloride, 800 mg, 1.53 mmol) were employed. In this case, the desired compound was obtained as pale yellow solids (385 mg, 82.7%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH2:13]([OH:16])[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OCCO
Reactant: COC(=O)c1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C2OCCO2)c1
Yield: 97.6 %

Procedure:
A mixture of methyl 3-formylbenzoate (2.5 g, 15.2 mmol), ethylene glycol (4.2 mL, 75 mmol) and para-toluenesulfonic acid monohydrate (0.29 g, 1.52 mmol) in toluene (60 mL) was heated at reflux under Dean and Stark conditions for 4 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated sodium hydrogen carbonate and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (3.09 g, 98%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([NH:7][NH:8][C:9](=[O:12])[CH2:10][CH3:11])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(#N)C>[CH2:10]([C:9]1[O:12][C:5]([C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([I:1])[CH:3]=2)=[N:7][N:8]=1)[CH3:11]
Reactant: CCC(=O)NNC(=O)c1cccc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1nnc(-c2cccc(I)c2)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
3-Iodo-N′-propionylbenzohydrazide (382 mg, 1.20 mmol) obtained in Step 2 was dissolved in acetonitrile (21 mL), and the mixture was stirred at 60° C. for 2 hours after adding triphenylphosphine (629 mg, 2.40 mmol), carbon tetrachloride (0.46 mL, 4.80 mmol), and triethylamine (0.33 mL, 1.54 mmol). After concentrating the mixture under reduced pressure, the residue was purified by silica gel column chromatography to give 2-ethyl-5-(3-iodophenyl)-1,3,4-oxadiazole (331 mg, 92%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:4][C:5](O)=[O:6].[BH4-].[Na+].II>C1COCC1>[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:4][CH2:5][OH:6]
Reactant: N[C@H](CC(=O)O)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: II
Agent: [BH4-]
Solvent: C1CCOC1
Product: N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(S)-3-Amino-4-(4-(trifluoromethyl)phenyl)butanoic acid hydrochloride (950 mg, 3.84 mmol) and NaBH4 (362 mg, 9.6 mmol) were dissolved in 20 mL THF and cooled to 0° C. A solution of I2 (974 mg, 3.84 mmol) in 5 mL THF was added at 0° C. over a period of 20 minutes. The cooling bath was removed and the reaction was heated at reflux over night. The reaction was cooled to room temperature and carefully hydrolyzed with MeOH until gas evolution ceased. The clear solution was evaporated in vacuo, 20 mL KOH (20%, aqueous) was added, and the reaction was stirred for 3 hours. The reaction was extracted with DCM (3×100 mL), dried over MgSO4 and evaporated. The title compound was obtained as a white solid and used without further purification in the next reaction. LCMS (API-ES) m/z (%): 234.0 (100%, M++H).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:12]=3[OH:26])[CH2:5]2)[O:3]C1.C(O)(=O)C(O)=O.CO.O>CCOCC>[CH3:25][C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH2:5][C:4](=[O:3])[CH2:9][CH2:8][C:7]=2[CH3:10])=[C:12]([OH:26])[CH:13]=1)([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC(C)(C)c1ccc(C2=C(C)CCC3(C2)OCCO3)c(O)c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(C)(C)c1ccc(C2=C(C)CCC(=O)C2)c(O)c1

Procedure:
A mixture of 4.08 g. (0.1 mol.) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-methyl-cyclohex-3-enone ethylene ketal, 50 ml. of 2 N oxalic acid and 50 ml. of methanol was stirred at 25° C. for 6 hours. The reaction mixture was added to 500 ml. of water-250 ml. of ether. The ether extract was washed once with 250 ml. of saturated sodium bicarbonate, once with 250 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified via column chromatography on 400 g. of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[N:26]1[CH:27]=[CH:28][C:23](/[CH:21]=[CH:22]/[C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Temperature: 100 °C
Yield: 49 %

Procedure:
A solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (2.0 g, 4.98 mmol), 4-vinylpyridine (0.69 mL, 6.47 mmol), diisopropylethylamine (1.74 mL, 9.96 mmol) and DMF (50 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (112 mg, 0.500 mmol) and P(o-tol)3 (457 mg, 1.50 mmol) were added and the reaction heated to 100° C. for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted with EtOAc (3×) and the combined organics washed with water (2×) and brine (2×). The organic layer was dried over MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 97:3 CH2Cl2/MeOH) to give 927 mg, 49% of the title compound which was used without further purification. MS ESI 380.2 [M+H]+, calcd for [C21H25N3O2Si+H]+ 380.18.
Reaction SMILES: [Br:1]Br.[Br-].[K+].[CH2:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+].S([O-])([O-])=O.[Na+].[Na+]>[Cl-].[NH4+].[NH4+].[NH4+].[NH4+].[Cl-].[Cl-].[Cl-].O>[CH2:5]([CH:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]1[Br:1])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: COc1cccc(Cc2ccccc2)n1
Agent: O=S([O-])[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Product: COC1=CC=CC(Cc2ccccc2)N1Br

Procedure:
A mixed solution of 17 ml of bromine, 90 g of potassium bromide and 450 ml of water was added dropwise into a mixture of 60 g of 2-benzyl-6-methoxypyridine (Production Example 2-b), 90 g of potassium bromide, 450 ml of water, 20 g of potassium hydroxide and 2.5 g of tetraammonium chloride over 2 hours under stirring in an ice bath. After stirring overnight as it was, sodium sulfite was added thereto and the mixture was extracted with hexane. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography to elute with 0.5-1.5% of ethyl acetate/hexane, to give 72.5 g of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23][CH2:24][CH2:25][CH2:26][NH2:27].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:22][S:23][CH2:24][CH2:25][CH2:26][NH:27][C:13]([CH:12]1[CH2:11][S:10][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Reactant: CSCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CSCCCNC(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C
Yield: 33.1 %

Procedure:
To a solution of 600 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid in 10 ml of tetrahydrofuran, there were added, at 4° C. or below, 200 mg of 3-methylthiopropylamine, 390 mg of 1-hydroxybenzotriazole and 440 mg of dicyclohexylcarbodiimide, in that order, and the mixture was stirred at room temperature for 3 hours. The resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 50 ml or ethyl acetate. The ethyl acetate solution was washed in sequence with 0.5M aqueous citric acid, water, saturated aqueous solution of sodium carbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 250 mg of N-(3-methylthiopropyl)-3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxamide. Trifluoroacetic acid (2 ml) was added to 250 mg of the thus-obtained compound with ice cooling, and the mixture was treated in the same manner as in Example 4 to give 130 mg of N-(3-methylthiopropyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride as an oil.