Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH:13]3[CH2:19][CH2:18][C:17]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:14]3=[O:30])[CH:12]=2)=[N:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.O>[F:24][C:20]1[C:17]2[CH2:18][CH2:19][CH:13]([N:11]3[CH:12]=[C:8]([C:5]4[N:4]=[CH:3][C:2]([C:34]5[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=5)=[CH:7][N:6]=4)[N:9]=[N:10]3)[C:14](=[O:30])[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:16]=2[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1C(n2cc(-c3ncc(Br)cn3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C1C(n2cc(-c3ncc(-c4ccncc4)cn3)nn2)CCc2c(F)cccc2N1CC(F)(F)F

Procedure:
3-[4-(5-Bromopyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (75 mg, 0.155 mmol), 4-pyridineboronic acid (28.5 mg, 0.232 mmol), Pd2(dba)3 (7.08 mg, 7.73 μmol), cesium carbonate (101 mg, 0.309 mmol), and X-phos (7.37 mg, 0.015 mmol) were combined in a microwave vial along with water (0.5 mL) and 1,4-dioxane (0.9 mL). The vessel was irradiated for 15 mins at 140° C. The vial was allowed to cool before being diluted with EtOAc and syringe filtered. The filtrate was concentrated and purified on column chromotagraphy to yield the desired product, 11 mg.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br.BrC[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.Cl>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccncc1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Br
Agent: Cl
Product: Clc1ccc2c(c1SCc1ccncc1)CCNCC2

Procedure:
Use a method similar to the Example 387, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-bromomethylpyridine hydrobromide to give, after hydrochloride formation by the General Procedure 2-2, the title compound as a white solid. MS (APCI+) m/z: 305 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:37](=[O:38])[N:4]2[C:5]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:6]([CH2:10][O:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:7][S:8](=[O:9])[C@H:3]12.C[Si](CC(N)=O)(C)C.[CH3:47][O:48][N:49]=[C:50]([C:54]1[N:58]=[C:57]([NH2:59])[S:56][N:55]=1)[C:51](O)=[O:52].P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CN(C)C=O>[CH3:47][O:48][N:49]=[C:50]([C:54]1[N:58]=[C:57]([NH2:59])[S:56][N:55]=1)[C:51]([NH:1][CH:2]1[C:37](=[O:38])[N:4]2[C:5]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:6]([CH2:10][O:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:7][S:8](=[O:9])[C@H:3]12)=[O:52]
Reactant: CN1CCN(C(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3S(=O)C2)CC1
Reactant: CON=C(C(=O)O)c1nsc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS(=O)[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.8 %

Procedure:
A mixture of benzhydryl 7-amino-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (1.33 g) and trimethylsilylacetamide (0.65 g) in dry methylene chloride (40 ml) was stirred for 2.5 hours at room temperature and then cooled to -20° C. (A solution). On the other hand, to a mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (0.50 g) in dry methylene chloride (12.5 ml) was added phosphorus oxychloride (1.6 ml) under ice-water cooling followed by stirring for 2 hours at room temperature. To the mixture was added a solution of N,N-dimethylformamide (0.99 ml) in dry methylene chloride (2 ml) followed by stirring for 50 minutes under ice-water cooling. Thus obtained solution was added to the A solution obtained above, followed by stirring for an hour at -30° to -20° C. The reaction mixture was poured into a mixture of a saturated aqueous solution of sodium bicarbonate (35 ml) and water (35 ml). The methylene chloride layer was separated therefrom and the remaining aqueous layer was further extracted with methylene chloride (50 ml×2). The methylene chloride layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure. The residue was washed with diethyl ether and dried to give benzhydryl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (1.3 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([CH3:18])=[C:7]([CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[C:8]([OH:10])=O)[CH2:3][CH2:2]1.[OH:19][C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[Si](C#N)(C)(C)C.[C-]#N.[K+]>CC#N>[CH:1]1([NH:4][C:5]2[C:6]([CH3:18])=[C:7]([CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[C:8]([C:21]2[CH:22]=[N:23][N:24]([CH3:25])[C:20]=2[OH:19])=[O:10])[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1NC1CC1
Reactant: Cn1nccc1O
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1NC1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under nitrogen, 0.50 g (1.9 mmol) of 3-cyclopropylamino-2-methyl-4-(methylsulfonyl)benzoic acid, 0.24 g (2.4 mmol) of 5-hydroxy-1-methylpyrazole and 0.43 g (2.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were dissolved in dry CH3CN. The mixture was stirred at RT for 5 h. 0.52 ml (3.7 mmol) of NEt3, 0.10 ml (0.7 mmol) of Me3SiCN and a spatula tip of KCN were added, and the mixture was stirred at RT for 1 day. The solvent was removed under reduced pressure, and the residue was taken up in CH2Cl2 and 10% strength H2SO4. The aqueous phase was extracted with CH2Cl2. The organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC. This gave 0.19 g of a beige solid of a purity of 90%.
Reaction SMILES: [O:1]=[C:2]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[CH:30]=[CH:29][C:27]=3[N:28]=2)[CH2:20][CH2:19]1)[C@@H:3]([NH:10]C(=O)OC(C)(C)C)[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.Cl.Cl.C(OCC)C>O1CCOCC1>[NH2:10][C@@H:3]([CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[C:2]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=4)[CH:30]=[CH:29][C:27]=3[N:28]=2)[CH2:22][CH2:23]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(-c4ccc(C(F)(F)F)cc4)cc3s2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(-c4ccc(C(F)(F)F)cc4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The (S)-tert-butyl 1-oxo-3-(thiophen-2-yl)-1-(4-(6-(4-(trifluoromethyl)phenyl)benzo[d]thiazol-2-yl)piperazin-1-yl)propan-2-ylcarbamate (96 mg) was dissolved in dry 1,4-dioxane (3 mL) and then HCl (4N in 1,4-dioxane, 1 mL) was added. The resulting mixture was stirred at room temperature overnight, then concentrated and chromatographed (93.5:6:0.5 DCM:MeOH:NH4OH) to yield a clear oil, which was added to 1N HCl/diethyl ether. The resulting white precipitate was collected by filtration to yield the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[C:11]([F:13])[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[F:14].[C-:15]#[N:16].[Na+].O>CS(C)=O>[C:15]([CH2:2][C:3]1[CH:12]=[C:11]([F:13])[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[F:14])#[N:16]
Reactant: [C-]#N
Reactant: Fc1cc(CCl)c(F)c2c1OCCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(F)c2c(c1F)OCCO2
Reaction time: 1 h

Procedure:
6-Chloromethyl-5,8-difluoro-1,4-benzodioxane (36.9 g, 0.183 mole) is dissolved in 500 ml of dimethylsulfoxide and 11.2 g (0.23 mole) of sodium cyanide added. This is stirred at 25° for 1 hour, and then poured into cold water. Extraction with ether, washing the extract with water, drying and concentration gives 6-cyanomethyl-5,8-difluoro-1,4-benzodioxane.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].OS(O)(=O)=O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([S:4][CH2:3][C:2](=[O:1])[CH3:14])[CH:6]=1)[CH3:21]
Reactant: CC(=O)CSc1cccc(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(SCC(C)=O)c1

Procedure:
3-(2-Oxo-propylsulfanyl)-benzoic acid from the previous reaction was dissolved in ethanol and a catalytic amount of conc. H2SO4 was added. The reaction was monitored by analytical TLC and when it was complete the reaction was concentrated to dryness and the resulting residue was purified via silica gel chromatography to give the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:19])=[C:6]([OH:18])[C:7]([CH3:17])=[CH:8][C:9]=1[O:10]C(=O)C(C)(C)C.[CH3:20][O:21][CH2:22]Cl>O1CCCC1>[Cl:3][C:4]1[C:5]([CH3:19])=[C:6]([O:18][CH2:20][O:21][CH3:22])[C:7]([CH3:17])=[CH:8][C:9]=1[OH:10]
Reactant: COCCl
Reactant: Cc1cc(OC(=O)C(C)(C)C)c(Cl)c(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)cc(O)c(Cl)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To 20 ml of an anhydrous tetrahydrofuran suspension containing 1.78 g of sodium hydride (55% by weight), 30 ml of a solution of 8.02 g of 3-chloro-2,6-dimethyl-4-pivaloyloxyphenol in anhydrous tetrahydrofuran were added dropwise, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 3.28 g of chloromethyl methyl ether were added and the mixture was stirred at room temperature for 13 hours. The reaction mixture was then concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. In 30 ml of methanol, 9.30 g of the residue were dissolved. To the resulting solution, 30 ml of a solution of 3.51 g of potassium hydroxide in methanol were added dropwise, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated by evaporation. The concentrate was neutralized with 3N hydrochloric acid and sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was separated and purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=10/1), whereby 5.65 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1Br.C(O)(C)C.O>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)nc(Br)c1Br
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(Br)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
4,5-Dibromo-2-(4-fluorophenyl)-1-(2-trimethylsilanyl-ethoxymethyl)imidazole (10.8 g; 25 mmol) are dissolved in THF (108 ml) and cooled to −78 C under argon. N-BuLi (15.6 ml; 1.6 M) is added under stirring within 15 min. After 30 min at −78 C, isopropanol (7.8 ml; 0.1 mol) is introduced dropwise and the mixture warmed to room temperature. Water is added to the reaction mixture and the aqueous phase extracted three times with ethyl acetate. The combined organic phases are washed with saturated NaCl-solution, dried over Na2SO4, filtered and evaporated to dryness, yielding the title compound as colorless oil (9.1 g; 95%).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>C(O)C.C(#N)C>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:28])[NH:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:5][CH:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Reactant: NCCN1CCOCC1
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCN3CCOCC3)cc2)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester (1.2 g) was dissolved in a co-solvent of ethanol (10 ml) and acetonitrile (20 ml), and 4-(2-aminoethyl)morpholine (0.82 g) was added. The reaction mixture was heated to reflux for 15 hours and cooled. After excess of water was added to the solution at 30° C. to precipitate the crystals, the solution was stirred for 1 hour. Then, the solution was again cooled slowly, stirred at 10~15° C. for 2 hours and filtered. The filtered crystal was washed with preheated water(40° C.) and was recrystallized using isopropanol and ether, filtered and dried to give 1.22 g (yield: 81%) of the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[OH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[C:26]([O:25][C:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:31][CH:30]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(C#N)cc21
Temperature: 115 °C
Yield: 75.3 %

Procedure:
A 500 ml flask equipped with a Claisen head and a condenser was charged with oven dried MS 4A powder (14.5 g), methyl 6-cyano-7-fluorochroman-4-carboxylate (14.11 g, 60.00 mmol), tert-butyl 4-hydroxybenzoate (14.57 g, 75.00 mmol), K2CO3 (20.73 g, 150.0 mmol), and 1-methyl-2-pyrrolidinone (120 mL). The mixture was degassed with Argon for 1 hour, then heated to 115° C. for 18 hours. The mixture was cooled to ambient temperature. The mixture was filtered through a CELITE pad and rinsed with EtOAc. The combined filtrates were washed with water. The EtOAc layer was dried over MgSO4, filtered through GF paper, and concentrated to a crude oil. The crude oil was purified on silica gel (EtOAc in hexanes gradient) to provide 18.5 g of the desired compound as semisolid.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][C:5]1[C:6](=O)[CH2:7][CH2:8][CH2:9][C:10]=1[O:11]CC(C)C.[CH2:18]([Li])[CH3:19]>CCOCC>[CH2:18]([C:6]1[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=1[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:17])[CH3:19]
Reactant: [Li]CC
Reactant: CC(C)CCC1=C(OCC(C)C)CCCC1=O
Solvent: CCOCC
Product: CCC1=C(CCC(C)C)C(=O)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A solution of isobutyl ether 8 (88.0 g, 370 mmol) in anhydrous ether (250 mL) was cooled to 0° C. in an ice bath and treated dropwise with ethyl lithium (650 mL). The resulting mixture was stirred at 0° C. for 2 hours and then at room temperature for 48 hours. The reaction mixture was slowly quenched with water (200 mL) and extracted with ether (2×200 mL). The combined organic layer was dried (Na2SO4) and concentrated under vacuum to provide 75 g of crude oil, which was purified by chromatography (silica gel; hexane/ether 4:1) to give 58.0 g (80.1%) of 9 as an oil: MS m/z 195 (M+1); 1H NMR (300 MHz, CDCl3) δ 2.4-2.3 (m, 4H), 2.3-2.2 (m, 4H), 1.95-1.85 (m, 2H), 1.6-1.5 (m, 1H), 1.2-1.1 (m, 2H), 1.1 (t, 3H), 0.9 (d, 6H); 13C NMR (CDCl3) δ 199.2, 159.9, 135.4, 39.0, 38.1, 30.0, 28.5, 27.8, 22.9, 22.6, 22.5, 12.4.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:28])C(=O)C1>CN(C=O)C.C1COCC1.CC(=O)OCC>[Br:28][C:4]1[N:3]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1ccn(S(=O)(=O)N2CCCCC2)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)n(S(=O)(=O)N2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of compound 4a (4.77 g, 15.9 mmol) in dry DMF (20 mL) and dry THF (20 mL) was added NBS (3.12 g, 17.5 mmol) in portions at 0° C. The mixture was stirred at rt overnight, diluted with EA, washed with water and brine, dried over Na2SO4, concentrated and purified by CC (PE/EA=1/0 to 15/1) to give compound 4b (4.2 g, 63%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23])=[O:17].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23])=[O:17]
Reactant: COCCNC(=O)Nc1cccc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COCCNC(=O)Nc1cccc(C=O)c1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
To a mixture of 2.64 g of oxalyl chloride and 50 ml of dichloromethane was added dropwise a solution of 3.24 g of dimethyl sulfoxide in 30 ml of dichloromethane at −60° C. for 10 minutes. After stirred at −60° C. for 20 minutes, a solution of 3.72 g of 3-[(2-methoxyethyl)aminocarbonylamino]benzyl alcohol in 30 ml of dichloromethane was added dropwise at −60° C. for 1 hour. After stirred at −60° C. for 15 minutes, 9.24 g of triethylamine was added dropwise at −60° C. for 25 minutes. After stirred at room temperature for 1 hour, water was added to the reaction solution, and the layers were separated. The organic layer washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to obtain 2.79 g of 3-[(2-methoxyethyl)aminocarbonylamino]benzaldehyde [Compound No. (i)] as a white crystal.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>>[C:11]([C:13](=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)=C1Cc2ccccc2C1

Procedure:
Prepared from 2-indanone and ethyl cyanoacetate according to a procedure identical to that used in Stage A of Example 15.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])=[CH:32][CH:31]=3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][S:12]2)=[CH:7][CH:6]=1.C(=O)([O-])O.[Na+]>Cl.CO.O1CCCC1>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:45])([F:46])[F:47])=[CH:32][CH:31]=3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][S:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCOc2ccc(OCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCOc1ccc(OCCSCCCC(F)(F)C(F)(F)F)cc1
Yield: 85.6 %

Procedure:
(3RS,4RS)-7-Methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methyl-4-{3-{4-[2-(4,4,5,5,5-pentafluoropentylthio)ethoxy]phenoxy}propyl}thiochroman (9) prepared in Step 7 (144 mg, 0.2 mmol) was dissolved in hydrochloric acid/methanol (1 ml) and tetrahydrofuran (0.1 ml), which was then stirred at room temperature for 4 days. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate and chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel column chromatography to give (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-{4-[2-(4,4,5,5,5-pentafluoropentylthio)ethoxy]phenoxy}propyl}thiochroman (11) (110 mg, yield 87%) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]4[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18]1)=[N:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[CH2:36]([C@@H:38]1[O:40][CH2:39]1)[Cl:37]>C1COCC1.CO>[Cl:37][CH2:36][C@H:38]([OH:40])[CH2:39][N:13]([CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:34][CH3:35])[N:9]=2)[N:4]=[CH:3][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1
Reactant: COc1ccc2ncc(F)c(CNCCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Reactant: ClC[C@H]1CO1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc(F)c(CN(CCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)C[C@@H](O)CCl)c2n1
Temperature: 70 °C
Yield: 52 %

Procedure:
A solution of the compound of Example 78 (0.135 g, 0.27 mmol) in THF/MeOH (1:1, 2 mL) was treated with (R)-epichlorohydrin (0.032 mL, 1.5 eq.). The mixture was heated at 70° C. overnight, concentrated in vacuo and purified by FC (EA/MeOH 19:1+1% NH4OH) to give the title compound as a colourless foam (0.1 g, 52% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:1]1[C:12](=[O:13])[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=[O:14]
Reactant: NCc1ccccn1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccn1
Yield: 86.2 %

Procedure:
2-Aminomethylpyridine (4.0 g, 37 mmol) and phthalic anhydride (5.5 g, 37 mmol) were dissolved in toluene (100 ml), and triethylamine (3.7 g, 36 mmol) was added thereto. The mixture was refluxed for 3 hrs. The solvent was evaporated, and the residue was recrystallized from hexane-ethanol to give the titled compound (7.6 g, 86%).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5]1)([OH:3])=[O:2].[CH2:19](OC(C1CCCN1)=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:19]([O:3][C:1]([CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)=[O:2])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: CCCCCCOC(=O)C1CCCN1
Product: CCCCCCOC(=O)C1CCNC1

Procedure:
By substituting the 3-carboxy-1-phenylmethyloxycarbonylpyrrolidine obtained in Example 10 for the 2-[(hexyloxy)carbonyl]pyrrolidine in the procedure of Example 1, 3-[(hexyloxy)carbonyl]pyrrolidine is obtained.