Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[C:13]([O:12][C:10]([N:1]1[CH2:23][CH2:22][CH2:21][CH2:20][N:2]1[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
A solution of di-tert-butyl hydrazine-1,2-dicarboxylate (10 g, 43.1 mmol) in dry N,N-dimethylformamide (25 ml) was added to a stirred suspension of sodium hydride (3.79 g of a 60% suspension in mineral oil, 95 mmol) in dry N,N-dimethylformamide (175 ml) at 0° C. under nitrogen. The reaction mixture was stirred for 30 minutes and then 1,4-dibromobutane (9.3 g, 43.1 mmol) was added within half a minute. The reaction was stirred at room temperature overnight. Then water (˜20 ml) was added carefully to the reaction mixture at room temperature, and stirring was continued for ca. 5 minutes. Thereafter the quenched reaction mixture was poured into 1 liter of water. The product was extracted twice with diethyl ether (200 ml), and the combined organic layers were washed with three times with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 14 g of crude tetrahydropyridazine-1,2-dicarboxylic acid di-tert-butyl ester. This was dissolved in diethyl ether (200 ml) and 4N hydrochloric acid in dioxane (108 ml, 431 mmol) was added. The resulting mixture was stirred overnight at room temperature. The thus formed white precipitate was isolated by filtration and dried under a flow of nitrogen to yield 4.6 g of crude product. Analysis by 1H NMR indicated that the reaction had not gone to completion. This crude product was combined with the crude product of a similar preparation, dissolved in dichloromethane (200 ml) and treated with 4N hydrochloric acid in dioxane (60 ml, 240 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and triturated with dry diethyl ether. The resulting precipitate was isolated by filtration and dried and a flow of nitrogen to yield 6.3 g of product, which was used without further purification in the next step.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=O)[CH3:11])[C:4]=2[N:3]=[CH:2]1.[CH3:13][NH2:14].Cl.O1CCOCC1.[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([NH:14][CH3:13])[CH3:11])[C:4]=2[N:3]=[CH:2]1
Reactant: CC(=O)c1cccc2[nH]cnc12
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CNC(C)c1cccc2[nH]cnc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of 1-(1H-benzoimidazol-4-yl)ethanone (72 mg, 0.449 mmol), methylamine (2M in THF; 2.25 mL, 4.50 mmol) and HCl in 1,4-dioxane (4M; 0.337 mL, 1.35 mmol) in MeOH (2.7 mL) was stirred at room temperature for 3 days before it was cooled to 0° C. and NaBH4 (20 mg, 0.539 mmol) was added in a single portion. The mixture was stirred at room temperature overnight before it was diluted with MeOH, stirred for 1 hour and concentrated in vacuo. The residue was purified by SiO2 chromatography providing [1-(1H-benzoimidazol-4-yl)-ethyl]-methyl-amine (46 mg).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(CC)C(C)C)(C)C.[OH:30][C:31]1([CH3:35])[CH2:34][NH:33][CH2:32]1>C(Cl)(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:33]1[CH2:34][C:31]([OH:30])([CH3:35])[CH2:32]1)=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CC1(O)CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(C)(O)C3)nc2c1C#N
Temperature: 100 °C
Yield: 92.1 %

Procedure:
Under nitrogen atmosphere, 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (216 mg, 0.753 mmol) was dissolved in N,N-dimethylsulfoamide (10 ml), then N,N-diisopropylethylamine (584 μl, 3.35 mmol) and 3-hydroxy-3-methylazetidine (132 mg, 1.51 mmol) dissolved in N,N-dimethylsulfoamide (5 ml) were added, followed by stirring under heat at 100° C. for 20 hours. After cooling, diluting with chloroform and washing with water, the organic layer was dried over anhydrous magnesium, sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (234 mg, 92%) as a white solid.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5]2)[CH2:3][N:2]1C(OC(C)(C)C)=O.Cl>C(Cl)Cl.O1CCOCC1>[CH2:3]1[C:4]2([CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:7][CH2:8]2)[CH2:1][NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)OCc3ccccc3)C2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CNC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-benzyl 2-tert-butyl 2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (705 mg, 2.0 mmol) in DCM (1 mL) was treated with hydrogen chloride (5 mL of 4 M, 20 mmol) in dioxane. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to obtain benzyl 2,7-diazaspiro[3.4]octane-7-carboxylate. LC/MS m/z 247.3 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:11]1[C:12]([CH:25]=[O:26])=[CH:13][C:14]2[C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[C:19]=2[CH:20]=1>CN(C)C=O>[CH3:21][C:18]1([CH3:22])[CH2:17][CH2:16][C:15]([CH3:23])([CH3:24])[C:14]2[CH:13]=[C:12]([CH:25]=[O:26])[C:11]([S:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:20][C:19]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(F)cc21
Reactant: Sc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(Sc3ncccn3)c(C=O)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
To a solution of 0.479 g (4.27 mmol) of 2-mercaptopyrimidine in 11 mL dimethylformamide was added 0.108 g (4.27 mmol) of 95% sodium hydride. After 20 minutes, 1.00 g (4.27 mmol) of 3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde was added and the resulting solution was heated at reflux. After 18 hours, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica (15% ethyl acetate/hexane) to afford 0.219 g (16%) of 5,5,8,8-tetramethyl-3-(pyrimidin-2-yl-thio)-5,6,7,8-tetrahydro-2-naphthaldehyde (mp=143.2-145.8). Horner-Emmons olefination, followed by ester saponification gave 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(mercaptopyrmidin-2-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 155 (mp=283-283.5). Substitution of 2-mercaptopyrimidine with 2-mercaptothiazole gave 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(mercaptothiazol-2-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 154 (MH+=450).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)=[O:8]>O.C(Cl)Cl.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[N:1]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium azide (32.5g.) in water (200ml.) was added to a solution of ethyl 4-(chloroacetyl)-phenylacetate (24.05g.) in methylene dichloride (200ml.). Benzyltrimethylammonium chloride (0.1g.) was added, and the bisphasic mixture was shaken for 4 hours at room temperature. The organic phase was separated, washed with distilled water (3 × 30ml.) dried and evaporated to give ethyl 4-(azidoacetyl)-phenylacetate as an oil showing a peak at 2120 cm-1 in its I.R. spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])[CH2:6][CH2:5]2.BrC1C=C2C(=C([N+:30]([O-:32])=[O:31])C=1)N(C1(C=CC=CC1)C(N)=O)CC2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:30]([O-:32])=[O:31])[CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])[CH2:6][CH2:5]2
Reactant: NC(=O)C1(N2CCc3cc(Br)cc([N+](=O)[O-])c32)C=CC=CC1
Reactant: NC(=O)c1ccccc1N1CCc2cc(Br)ccc21
Product: NC(=O)c1ccccc1N1CCc2cc(Br)cc([N+](=O)[O-])c21

Procedure:
It is predicted that if the 2-(5-bromo-indolin-1-yl)benzamide of Example 13a is treated in the manner of Example 1b that 1-(5-bromo-7-nitro-1-indolinyl)benzamide will be obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=3[CH:52]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.340 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.193 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.30 (1:1 EtOAc-heptane); Rt=5.99.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[CH3:25])([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:1][C:2]([F:26])([F:27])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:36]([CH3:35])(=[O:38])=[O:37])[C:21]([F:23])([F:22])[F:24])[CH:12]=[CH:11][C:10]=1[CH3:25])([O:8][S:36]([CH3:35])(=[O:38])=[O:37])[C:4]([F:7])([F:6])[F:5]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C(O)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4.25 g (10 mmol) of 2,4-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-toluene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 2.86 g (25 mmol) of methanesulfonyl chloride were added dropwise at 5° to 10° C. The mixture was stirred for 16 hours at room temperature, separated off from the precipitated salt, washed with water, dried and evaporated down. The residue was chromatographed over a silica gel column with methylene chloride/n-hexane (1:1). After the eluate had been evaporated down, 2.9 g of 2,4- bis-(2,2,2-trifluoro-1-methanesulfonyloxy-1-trifluoromethylethyl)-toluene were obtained (colorless crystals, m.p.: 107° C.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([NH:14][O:15][CH3:16])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.O>CN(C=O)C>[CH3:16][O:15][N:14]([S:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)(=[O:12])=[O:13])[C:23]1[CH:22]=[CH:21][C:20]([N+:25]([O-:27])=[O:26])=[CH:19][C:18]=1[Cl:17]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CONS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1Cl)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in 3.0 ml of DMF, 3,4-dichloro-N-methoxybenzenesulfonamide (0.56 g (2.19 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3-chloro-4-fluoronitrobenzene (0.35 ml (1.99 mmol)) was added and the mixture was stirred for one hour under cooling with ice and 3 hours at room temperature. Then, water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed twice with water and the ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.56 g (68%) of the title compound as pale yellow-white crystals.
Reaction SMILES: C([O:3][C:4]([C@:6]1([NH:23][C:24](=[O:34])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][C@H:10]([S:12][C:13]2[NH:17][CH:16]=[N:15][N:14]=2)[C@@H:9]2[C@H:7]1[C@H:8]2[C:18]([O:20]CC)=[O:19])=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[C:30]([O:29][C:27]([NH:26][CH2:25][C:24]([NH:23][C@@:6]1([C:4]([OH:5])=[O:3])[CH2:11][C@H:10]([S:12][C:13]2[NH:17][CH:16]=[N:15][N:14]=2)[C@@H:9]2[C@H:7]1[C@H:8]2[C:18]([OH:20])=[O:19])=[O:34])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2Sc1nnc[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@]1(C(=O)O)C[C@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.4 %

Procedure:
Dissolve diethyl(1R,2S,4S,5R,6R)-2-[[-2-(tert-butoxycarbonylamino) acetyl]amino]-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.420 g, 0.84 mmol) in tetrahydrofuran (7 mL) then add 2.5M lithium hydroxide (6.7 mL, 16.88 mmol). Stir the mixture at room temperature for 3.5 hours. Dilute the reaction mixture with water and wash with ethyl acetate. Discard the organic layer. Adjust the aqueous phase to pH=2 with 1N hydrochloric acid and extract with ethyl acetate. Dry the organic phase over magnesium sulfate, filter and concentrate to dryness to yield the title compound as a white solid (250 mg, 66%). MS (m/z): 442 (M+1), 464 (M+23).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=[C:15]([CH:23]=[O:24])C=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:15][CH:23]=[O:24])=[CH:5][CH:4]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Product: O=CC=Cc1ccc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 7 by substituting 6-trifluoromethyl-3-pyridinecarboxaldehyde for the 3-quinolinecarboxaldehyde of Reference Example 7. MS 202 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C(O)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Br)c1

Procedure:
A mixture of 3.8 g (16.33 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile and 3.7 g (20 mmol) of 3-bromo-4-fluoroaniline in 200 mL of ethanol was refluxed for 3 hr. After the solvent was removed, the residue as dissolved in ethyl acetate and washed with sodium bicarbonate. The product was collected as a pale yellow solid, 6.5 g (71%); ESMS m/z 387.3, 389.2, mp 269-270° C. (dec).
Reaction SMILES: [CH3:1]Cl.[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH2:8][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:14])=[CH:6][C:5]=1[O:21][CH3:22].[Br-].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH2:8][C:9]([CH3:1])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]2=[O:14])=[CH:6][C:5]=1[O:21][CH3:22]
Reactant: CCl
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 35 ml glass pressure bottle, fitted with an efficient magnetic stirrer was charged with 25 ml of toluene. Methyl chloride (1.01 g, 20 mmole) were dissolved in the toluene and to this solution there were added 0.61 g (2 mmole) of 6,7-dichloro-5-methoxy-2-phenyl-1-indanone, 0.21 g (0.4 mole) of N-p-(trifluoromethylbenzyl) cinchoninium bromide and 5 ml of 50% aqueous sodium hydroxide. The reaction mixture was sealed with a screw cap and vigorously stirred for 18 hours at room temperature (22°-25° C.). The reaction mixture was then diluted with 25 ml of toluene and 15 ml of water. The aqueous layer was separated and the toluene layer was washed twice with 25 ml of 4N hydrochloric acid. An aliquot of the toluene solution was concentrated in vacuo to dryness on a rotary evaporator. An LC assay indicated a 98% yield while an NMR assay using the chiral shift reagent [tris-[3-heptafluoropropylhydroxymethylene)-d-camphorato]europium (III)] showed a (+):(-) isomer ratio of 95.3:4.7.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][C:14]=3[F:22])=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:27]#[C:26][CH2:25][OH:28])=[CH:15][C:14]=3[F:22])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(4-chlorobenzyl)-8-fluoro4-hydroxy-6-iodo-3-quinolinecarboxamide of Preparation No. 1 (0.466 g) in 15 mL diethylamine is added CuI (0.010 g) and (Ph3P)2PdCl2 (0.035 g). Propargyl alcohol (0.058 mL) is then added and the reaction is stirred overnight at room temperature. The diethylamine is removed in vacuo. The residue is partitioned between EtOAc and water. The insoluble material is filtered off and saved. The organic layer is washed with brine, dried and condensed. The residue is combined with the insoluble material and adsorbed onto silica and chromatographed, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed to yield 0.192 g of the desired product as a tan solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[S:3][N:2]=1>[O-2].[O-2].[Mn+4]>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[S:3][N:2]=1
Reactant: OCc1cnc2snnc2c1
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1cnc2snnc2c1
Yield: 51.6 %

Procedure:
The alcohol (iv) (0.10 g) was oxidised with manganese dioxide to afford a solid (51 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1

Procedure:
64.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 4-methoxy-benzoic acid to give (R)-3-[(4-methoxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow oil. MS 335.1 ([M+H]+)
Reaction SMILES: [OH:1][C@@H:2]([C@@H:23]([C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH3:24])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13]C(=O)C2C=CC=CC=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[OH:1][C@@H:2]([C@@H:23]([C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH3:24])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([OH:13])[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2
Reactant: Cc1cccc([C@@H](C)[C@H](O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc([C@@H](C)[C@H](O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The crude alcohol, {(1S,5R,6R,7R)-6-[(1E,3R,4R)-3-hydroxy-4-(m-tolyl)-1-pentenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one} (649.9 g) synthesized in Example 4 was dissolved in methanol (740 mL), potassium carbonate (116.3 g) was added, and the mixture was stirred at room temperature for 17 hr. Acetic acid was added to adjust to pH 7, methanol was evaporated, water was added, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-0/1) to give the title compound (22.3 g). The structural property was as described below.
Reaction SMILES: C12BC(CCC1)CCC2.[C:10]1([CH3:35])[CH:15]=[CH:14][C:13]([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]#[N:29])=[CH:25][CH:26]=3)[C:21]([CH:30]3[CH2:32][CH:31]3[CH:33]=[CH2:34])=[CH:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[OH-:36].[Na+].OO>C1COCC1.C(O)C>[OH:36][CH2:34][CH2:33][CH:31]1[CH2:32][CH:30]1[C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[N:19]([S:16]([C:13]2[CH:12]=[CH:11][C:10]([CH3:35])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH:20]=1
Reactant: C=CC1CC1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(C3CC3CCO)c3cc(C#N)ccc32)cc1
Temperature: 30 °C
Yield: 45 %

Procedure:
9-Borabicyclo[3.3.1]nonane (4.1 ml of 0.5 M THF solution, 2.05 mmol) was added drop wise under a nitrogen atmosphere to a stirred solution of 1-(toluene-4-sulfonyl)-3-(2-vinyl-cyclopropyl)-1H-indole-5-carbonitrile (735 mg, 2.01 mmol) in dry THF (6 ml). The solution was heated to 30° C. for 6 hr and then cooled to 20° C. Absolute ethanol (12 ml), sodium hydroxide (2.6 ml of a 1N solution, 2.6 mmol), and hydrogen peroxide (0.85 ml of a 30% solution) were added sequentially to the stirred solution. The mixture was heated to 40° C. for 1 hr and then cooled to room temperature. Sodium hydroxide (2 ml of a 1N solution) was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using 3% acetone in methylene chloride as the eluent to give 3-[2-(2-hydroxy-ethyl)-cyclopropyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (300 mg, 45%). 1H NMR (300 MHz, CDCl3): δ8.01 (d, 2H), 7.97 (s, 1H), 7.73 (d, 1H), 7.28 (s, 1H), 7.24 (d, 2H), 3.80 (m, 2H), 2.35 (s, 3H), 1.74-1.62 (m, 4H), 1.08 (m, 1H), 0.90 (m, 1H), 0.83 (m, 1H). MS m/e 381.17 (MH+).