Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+]>O1CCCC1.O>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)[C:4]([OH:26])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid ethyl ester (707 mg, 1.80 mmol in tetrahydrofuran/water (24 mL, 3:1) was treated with lithium hydroxide (166 mg, 3.97 mmol). The reaction was stirred at 25° C. for 24 h. At this time, the reaction concentrated in vacuo. The residue was diluted with water (25 mL) and extracted with diethyl ether (1×15 mL). The aqueous layer was acidified to pH=1 with a 2N aqueous hydrochloric acid solution, and extracted with chloroform (3×25 mL). The combined organic layers were washed with water (1×25 mL) and a saturated aqueous sodium chloride solution (3×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (426.7 mg, 65%) as a white solid: mp 122–123° C.; EI-HRMS m/e calcd for C16H19F3O4S (M+) 364.0956 found 364.0956.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[OH:23][CH2:22][CH2:21][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: OCCCl
Reactant: CCOC(=O)C1=C(Nc2ccccc2O)OCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(Nc2ccccc2OCCO)OCC1=O
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step, 2-chloroethanol (0.038 mL, 0.57 mmol) and potassium carbonate (0.11 g, 0.80 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 90° C. for 2 days. Cooled to ambient temperature, ethyl acetate was added to the reaction mixture, the organic layer was washed with aqueous 5% citric acid solution, water and brine, dried over magnesium sulfate and concentrated. To the residue, tert-butyl methyl ether was added to precipitate the product. The precipitate was collected by filtration, washed with hexane then dried to afford ethyl 2-{[2-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.041 g, y. 35%).
Reaction SMILES: Cl[O-:2].[Na+].Br[O-].I[O-].[N+:8]([C:11]1[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(O)(=O)C>[N+:8]([C:11]1[S:15][C:14]([C:16]([OH:2])=[O:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: [O-]Cl
Agent: [Na+]
Agent: [O-]Br
Agent: [O-]I
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Yield: 75 %

Procedure:
It has also been observed, in accordance with another aspect of the present invention, that a mixture of halogen and alkali metal hydroxide i.e. an alkali metal hypohalide such as sodium hypochlorite, hypobromite or hypoiodite when it is added to an aqueous suspension of 5-nitro-2-formyl-thiophene maintained at a pH between 4.5 and 6.5 by means of acetic acid or an acetic acid/alkali metal acetate mixture, provides pure 5-nitro-2-thenoic acid in a yield of at least 75%.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCCl.C([O:16][C:17]([C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22](=[O:29])[N:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]=1[CH3:36])=[O:18])(C)(C)C>>[CH3:36][C:20]1[N:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22](=[O:29])[CH:23]=[C:24]([C:25]([F:26])([F:28])[F:27])[C:19]=1[C:17]([OH:18])=[O:16]
Reactant: Cc1c(C(=O)OC(C)(C)C)c(C(F)(F)F)cc(=O)n1-c1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)c(C(F)(F)F)cc(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (100 uL, 1 mmol) in 1,2-dichloroethane (200 uL, 2 mmol) was added to 2-methyl-6-oxo-1-phenyl-4-trifluoromethyl-1,6-dihydro-pyridine-3-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol). The obtained solution was stirred at r.t. overnight and evaporated. The residue was partitioned between 2M NaOH (4 mL) ethyl acetate (2×2 mL) to remove traces of the unreacted ester. The aqueous phase was acidified and the product extracted with ethyl acetate (2×3 mL). The combined organic solution was washed with brine, dried (MgSO4) and evaporated, yield 19.4 mg, 50%. LC-MS (m/z) 298.4 (MH+); tR=0.80 (method C).). 1H NMR (500 MHz, DMSO-d6): 1.99 (s, 3H, Me), 3.56 (br., CO2H+H2O), 6.86 (s, 1H, C5-H), 7.36 (d, J=7.3 Hz, 2H, two ortho-H of Ph), 7.50 (t, J=7.4 Hz, 1H, para-H of Ph), 7.56 (t, J=7.5 Hz, 2H, two meta-H of Ph).
Reaction SMILES: [C-:1]#[N:2].[K+].[S:4]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5]1.C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][S:4][CH:5]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1ccsc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#CC(O)c1ccsc1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of KCN (18.6 g, 286 mmol) in methanol (100 mL) was added thiophene-3-carbaldehyde (20 mL, 178 mmol) at 0° C. under nitrogen atmosphere. Then acetic acid (4.4 mL) was added dropwise at 0° C. After 30 minutes, the mixture was warmed to 15° C. and stirred for 20 hours. NaHCO3 (15 g) was added. The mixture was concentrated and extracted with ethyl acetate (200 mL). The organic mixture was washed with water (3×25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:10) to afford hydroxy-thiophen-3-yl-acetonitrile. (Yield 15 g, 60%). LC-MS: [M+Na]+ 162.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:13][NH:14][C:15](=[O:16])[C:11]=2[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[H-].[Na+].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:12]2[CH2:13][N:14]([CH2:35][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=3)[C:15](=[O:16])[C:11]=2[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: COc1ccc(COc2c3c(c(OC)c4cccnc24)CNC3=O)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c3c(c(OC)c4cccnc24)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.6 %

Procedure:
5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 304 (25.4 mg, 0.073 mmol,) was dissolved in dimethylformamide (0.4 ml) and cooled to 0° C. Sodium hydride (3.6 mg, 0.095 mmol) was added, followed by stirring at 0° C. for 5 minutes. 4-trifluoromethyl-benzylbromide (21.0 mg, 0.088 mmol) was added and the reaction mixture was allowed to warm to room temperature and kept at room temperature with stirring for 5 minutes. It was cooled to 0° C., quenched with acetic acid (0.030 ml), and concentrated in vacuo. The mixture was diluted with ethyl acetate, washed twice with water, once with brine, dried over magnesium sulfate, and concentrate in vacuo. The residue was purified by silica gel chromatography (99/1—ethyl acetate/acetic acid) to afford 5-Methoxy-9-(4-methoxy-benzyloxy)-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 305 (13 mg, 0.026 mmol, 35%). 1H NMR δ 9.15 (dd, 1H), 8.60 (dd, 1H), 7.60 (m, 4H), 7.40 (d, 2H), 6.80 (d, 2H), 5.85 (s, 2H), 4.80 (s, 2H), 4.42 (s, 2H), 3.98 (s, 3H), 3.86 (s, 3H). MS: 509.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:10][C:8](=[O:9])[NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: COC[C@H](C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N[C@@H](C)COC

Procedure:
A solution of (S)-1-methoxy-2-propylamine in tetrahydrofuran was allowed to undergo the reaction with ethyl chloroformate in the presence of triethylamine to obtain [(1S)-2-methoxy-1-methylethyl]carbamic acid ethyl ester.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[N:21]3[N:22]=[C:23]([Cl:33])[CH:24]=[C:25]([CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:20]3=[N:19][C:18]=2[CH3:34])=O)=[C:11]([F:35])[CH:10]=1.FC(F)(F)C(O)=O>>[ClH:8].[Cl:33][C:23]1[CH:24]=[C:25]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:20]2[N:21]([C:17]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=3[F:35])=[C:18]([CH3:34])[N:19]=2)[N:22]=1
Reactant: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1Cc1ccc(Cl)cc1F
Product: Cl

Procedure:
At 26° C., combine triethylsilane (110 g, 946 mmol) and (4-chloro-2-fluorophenyl)(6-chloro-2-methyl-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-3-yl)methanone (50.1 g, 117.06 mmol) to form a solution. Add trifluoro acetic acid (150 mL, 1.98 mol) to the reaction mixture then heat at 78° C. for 24 h. Cool the reaction to ambient temperature and separate the mixture to remove the top layer. Dissolve the bottom layer with ethyl acetate (1 L) and adjust the pH to 11 with sodium hydroxide (4 N, 500 mL). Separate the organic layer and add HCl (4 M in ethyl ether) to the organic layer to form the HCl salt. Filter and dry the HCl salt. (100 g (96%); mp=237-238° C.; M+=409).
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:21][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[CH2:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccccc2C(OCC2CO2)N1c1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCN(CC(O)COC2c3ccccc3C(=O)N2c2ccccc2)CC1
Yield: 127.3 %

Procedure:
A solution of 3-(2,3-epoxypropoxy)-2-phenyl-isoindolin-1-one (8.4 g.) and 1-methylpiperazine (3.6 g.) in anhydrous toluene (84 cc.) is heated under reflux for 3 days. After cooling, the reaction mixture is washed with water (2 × 50 cc.) and then the organic solution is extracted with 1N hydrochloric acid (55 cc.) and water (3 × 20 cc.). The aqueous and acid solutions are combined and are rendered alkaline by addition of 1N sodium hydroxide solution (55 cc.). The oil which separates out is extracted with methylene chloride (150 cc.) and then the organic solution obtained is dried over sodium sulphate and concentrated to dryness under reduced pressure. The residual oil is dissolved in ethanol (20 cc.) and the resulting solution is added to a hot solution of fumaric acid (5.85 g.) in ethanol (80 cc.). The product which crystallises on cooling is filtered off and then washed with ethanol (30 cc.) and di-isopropyl ether (40 cc.). After drying, 3-[2-hydroxy-3-(4-methylpiperazin-1-yl)-propoxy]-2-phenyl-isoindolin-1-one acid difumarate (14.5 g.), melting at 194° C., is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[CH2:24][O:25][CH3:26].[C:27](=O)([O-])[O-:28].[K+].[K+]>COCCOC.CO>[CH3:26][O:25][CH2:24][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[CH2:2][O:28][CH3:27])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: O=C([O-])[O-]
Reactant: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1COC
Yield: 27.7 %

Procedure:
A mixture of 4-chloromethyl-8-(2,6-dichlorobenzoylamino)-3-methoxymethylquinoline (70 mg) and potassium carbonate (26 mg) in 1,2-dimethoxyethane and methanol was refluxed for 2 hours. After cooling, the mixture was partitioned between saturated ammonium chloride solution and dichloromethane, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and crystallized from isopropyl alcohol to give 3,4-bis(methoxymethyl)-8-(2,6-dichlorobenzoylamino)quinoline (19.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][C:27]=1[Cl:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[ClH:21].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([O:18][C:25]4[CH:24]=[CH:23][C:22]([Cl:21])=[C:27]([Cl:28])[CH:26]=4)[CH2:16][CH2:17]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: OC1CCN(CCCc2noc3cc(F)ccc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cl
Product: Fc1ccc2c(CCCN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)noc2c1
Temperature: 25 °C

Procedure:
To a solution of 6.4 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxypiperidine, 3.7 g of 3,4-dichlorophenol and 6.6 g of triphenylphosphine in 200 ml of benzene, cooled with an ice bath, was slowly added over one hr a solution of 4.4 g of diethyl azodicarboxylate in 50 ml of benzene. After stirring twenty hrs at ambient temperature, the reaction mixture was filtered and the filtrate was concentrated. The residue was treated with ethereal hydrogen chloride to yield a salt. The salt was rebasified to given an oil, which was purified by column chromatography (silica gel, tetrahydrofuran). The purified oil was treated with ethereal hydrogen chloride, and the resultant salt was recrystallized from ethyl acetate/methanol to give 2.4 g (23%) or product, mp 212°-214° C.
Reaction SMILES: [P:1]([O:5][CH2:6][C:7]([O-:9])=[O:8])([OH:4])([OH:3])=[O:2].[CH:10]1([NH3+])[CH2:15]CCC[CH2:11]1.C1([NH3+])CCCCC1.C1([NH3+])CCCCC1.P([O:35][CH2:36]C([O-])=O)(O)(O)=O.P([O:44][CH2:45]C([O-])=O)(O)(O)=O>CO>[P:1]([O:5][CH2:6][C:7]([OH:9])=[O:8])([OH:4])([OH:3])=[O:2].[CH3:36][O:35][C:10]([O:44][CH3:45])([CH3:15])[CH3:11]
Reactant: O=C([O-])COP(=O)(O)O
Reactant: [NH3+]C1CCCCC1
Solvent: CO
Product: COC(C)(C)OC
Product: O=C(O)COP(=O)(O)O

Procedure:
PGH is synthesized from tri(monocyclohexylammonium) 2-phosphoglycolate (Sigma-Aldrich Chemie GmBH, Germany), which is first converted into the free acid form using Dowex 50W-H+. Treatment of the 2-phosphoglycolic acid with 2,2-dimethoxypropane in methanol yielded the methyl ester 2PG, which is converted to PGH (Collins, K. D. (1974) J. Biol. Chem. 249:136-142). Purification of PGH to homogeneity is done on a DEAE Sephadex A-25 column using a 0-0.4 M lithium chloride gradient. Two consecutive purification columns are needed to obtain a product free of 2PG. PGH is isolated from LiCl by precipitation with barium salts (Lewis, D. J. & Lowe, G., (1977) Eu.r.J. Biochem. October, 17;80(1):119-33). The purity of the barium salt of PGH was confirmed by P NMR and H NMR and mass spectrometry. PGH solutions are prepared as described (Lewis & Lowe, 1977), and the concentration of dissolved PGH is determined spectrophotometrically (Collins, 1974).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:10][CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[CH2:4]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21].C(N(CC)C(C)C)(C)C>C(#N)C>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[N:8]1[CH2:9][CH:5]2[CH2:4][CH:3]([OH:2])[CH2:10][CH:6]2[CH2:7]1
Reactant: OC1CC2CNCC2C1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CC3CC(O)CC3C2)c(F)c1

Procedure:
The octahydro-5-hydroxycyclopenta[c]pyrrol hydrochloride (44.4 mmol) prepared in the step 1 was dissolved in 100 ml of acetonitrile, and 4.91 ml (44.4 mmol) of 1,2-difluoro-4-nitrobenzene and 23.20 ml (133.2 mmol) of N,N-diisopropylethylamine were added, and the mixture was heat to reflux for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was concentrated under reduced pressure to remove the solvent. The solvent-free concentrate was dissolved in ethyl acetate, and washed with distilled water, and then, the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound, of which NMR data is as follow.
Reaction SMILES: C[C:2]1C=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].BrC1C=CC=C2C=1C=C[N:27]2S(C1C=NC=CC=1)(=O)=O.C([Sn](CCCC)(CCCC)C=C)CCC.CO>CC#N.C(Cl)Cl>[N:27]1[CH:6]=[CH:5][CH:4]=[C:3]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:2]=1
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1C
Reactant: O=S(=O)(c1cccnc1)n1ccc2c(Br)cccc21
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccnc1
Yield: 80 %

Procedure:
The experimental for Intermediate 15 was followed using 4-bromo-1-(pyridin-3-ylsulfonyl)-1H-indole (285 mg, 0.85 mmol; Intermediate 24) in dry MeCN (5 mL, one vial), tributyl(vinyl)stannane (0.494 mL, 1.69 mmol) and Pd(PPh3)2OAc2 (32 mg, 0.042 mmol). Flash chromatography (1% MeOH in DCM) afforded the title compound (208 mg, 80%) as a yellow sticky oil. MS (ESI+) for C15H12N2O2S m/z 285 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([F:14])[C:8]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.CC(OC)(C)C>C(Cl)(Cl)(Cl)Cl.C1CCCCC1>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:17])=[C:9]([F:14])[C:8]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)OC(C)(C)C)c(F)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: COC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)c1ccc(CBr)c(F)c1F
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of 2,3-difluoro-4-methyl-benzoic acid tert-butyl ester (17.3 g, 75.9 mmol) and N-bromosuccinimide (13.5 g, 75.9 mmol) in carbon tetrachloride (250 mL) was degassed for 10 minutes. AIBN (1.2 g, 7.32 mmol) was added and the reaction mixture was stirred at reflux for 18 hours before being cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue which was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, TBME in cyclohexane) to afford the title compound as a colourless oil (16.7 g, contaminated by 25% of starting material). 1H NMR (CDCl3, 400 MHz) 7.61 (1 H, ddd, J=8.3, 6.4, 2.1 Hz), 7.18 (1 H, ddd, J=8.1, 6.4, 1.8 Hz), 4.49 (2 H, d, J=1.3 Hz), 1.59 (9 H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][OH:13])[CH2:10][OH:11].[C:15](OC(=O)C)(=[O:17])[CH3:16].[C:22](OCC)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:15]([O:11][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:14])[CH2:12][O:13][C:22](=[O:24])[CH3:23])(=[O:17])[CH3:16]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: OCC(O)(CO)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 ml of pyridine was dissolved 10 g of 2-(2,4-difluorophenyl)-1,2,3-propanetriol. To the resulting solution was added dropwise 1.1 g of acetic anhydride at room temperature. After the dropping, the resulting liquid was stirred at room temperature for 1 hour. Then, to the reaction mixture was added 50 ml of ethyl acetate, and an organic layer was separated therefrom. After the organic layer was washed with 1N aqueous solution of hydrochloric acid and further washed with water and saturated aqueous solution with sodium chloride. Then the organic layer was dried over anhydrous sodium sulfate. The resulting organic layer was filtered and the solvent was removed under reduced pressure. Thus obtained concentrate was purified by column chromatography on silica gel (hexane: ethyl acetate=1:1) to give 12.5 g of the desired compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[OH-].[Na+].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[ClH:22].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH:2]2[CH2:11][CH:10]3[N:5]([CH2:6][CH2:7][C:8]4[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=43)[CH2:4][CH2:3]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)c3ccc(Cl)cc3)CCN1CC2
Product: Cl
Yield: 64 %

Procedure:
A mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (8 g, 0.03 mole), 200 ml of toluene and 80 ml of 20% NaOH was cooled to 10° in an ice bath at which point 4-chlorobenzoyl chloride (5.5 g, 0.03 mole) was added dropwise with stirring. The mixture was stirred in the cold for 1 hour whereupon the solid was collected by filtration and chromatographed over silica gel using ethyl acetate-methanol-chloroform (3:1:1) as eluant. The major fraction (6.2 g) was converted to the HCl salt with hydrogen chloride in 2-propanol-ethyl acetate and was recrystallized from methanol-ethyl acetate twice to yield 4.2 g of the desired product, m.p. (decomposed at 253°-4°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR23##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2)#[N:2].[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:9]1)=[O:20])([CH3:15])[CH3:14]
Reactant: N#Cc1ccc2c(c1)CCNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(C#N)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-cyano-1,2,3,4-tetrahydro-isoquinoline (CA [166398-34-1]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).