Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:25][CH3:26])(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].CN(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH:19]([C:18]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ncc(Br)cc1[N+](=O)[O-]

Procedure:
Prepared according to procedure G using 5-bromo-2-chloro-3-nitropyridine (25 g, 105 mmol) and potassium carbonate (44 g, 316 mmol), dimethyl malonate (18 mL, 158 mmol) in DMF (105 mL, 105 mmol). After purification dimethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate was obtained as a dark liquid. Mass Spectrum (ESI) m/e=333 [(M+1) (79Br)] and 335 [(M+1) (81Br)].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([F:21])=[C:12]3[C:17](=[CH:18][C:19]=2[F:20])[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:22])=[N:4][CH:3]=1.[N:23]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[C:11]([F:21])=[C:12]4[C:17](=[CH:18][C:19]=3[F:20])[N:16]=[CH:15][CH:14]=[CH:13]4)[N:23]=[N:22][C:5]2=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)nc1NCc1c(F)cc2ncccc2c1F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc2ncccc2c(F)c1Cn1nnc2ncc(Br)nc21
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 6-bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1.5 g, 4.10 mmol) in acetic acid (50 mL) and water (10 mL) was added a solution of sodium nitrite (283 mg, 4.10 mmol) in water (3 mL). After stirring at it for 3 h, the solvent was removed in vacuo, the residue was taken with NaHCO3 (aq.), extracted with CH2Cl2. The organic layer was washed with NH4Cl (aq.), dried over Na2SO4, filtered and concentrated in vacuo and purified by silica gel chromatography with hexanes:EtOAc to provide 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (1.02 g, 65%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.99 (d, 1H), 8.79 (s, 1H), 8.43 (d, 1H), 7.65 (d, 1H), 7.49 (m, 1H), 6.13 (s, 2H). LCMS (method B): [MH]+=376.8, tR=2.23 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15]Cl.[Na+].[Cl-]>O>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClCCCCCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCCOc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 81 %

Procedure:
A 1 L flask provided with a stirrer was charged with 128.6 g (1.0 mol) of p-chlorophenol (available from Tokyo Chemical Industry Co., Ltd.), 52.0 g (1.3 mols) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 152.4 g (1.2 mols) of 1,4-dichlorobutane (available from Tokyo Chemical Industry Co., Ltd.) and 300 g of water. The content was maintained at 80° C. for 4 hours. Then the reaction liquid was cooled to room temperature, and deposited NaCl, produced by side reaction, was filtered off. The organic phase was separated and subjected to distillation under reduced pressure to give 177.4 g of the target p-(4-chlorobutoxy)chlorobenzene (yield: 81%, purity: 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.O>CO.[BH4-].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]([OH:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:9]2=[O:10])=[CH:15][CH:16]=1.[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[C:6](=[O:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]2[OH:10]
Reactant: CC(C)CN1C(=O)c2ccc(Cl)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)c2cc(Cl)ccc2C1O
Product: CC(C)CN1C(=O)c2ccc(Cl)cc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 198.3 %

Procedure:
5-Chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are prepared as described in Example 1, starting with 12 g of 4-chloro-N-isobutylphthalimide in 100 cm3 of methanol and 3 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and 100 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C. The aqueous phase is extracted twice with 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 12 g of 5-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder. (Rf=0.15, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.Cl[CH2:15][CH2:16][CH2:17]I.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])([O-])=O.[K+].[K+].[CH2:31]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:32][CH2:33][CH3:34]>C(#N)C.O>[CH2:31]([CH:35]1[CH2:40][CH2:39][N:38]([CH2:15][CH2:16][CH2:17][N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][C:8]2=[O:13])[CH2:37][CH2:36]1)[CH2:32][CH2:33][CH3:34]
Reactant: ClCCCI
Reactant: CCCCC1CCNCC1
Reactant: COc1ccc2c(c1)CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCC1CCN(CCCN2C(=O)CCc3cc(OC)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Methoxy-3,4-dihydro-1H-quinolin-2-one (108 mg, 0.61 mmol), 1-chloro-3-iodopropane (64 μl, 0.6 mmol) and Cs2CO3 (290 mg, 0.9 mmol) in acetonitrile (2 mL) were shaken at 60° C. for 14 h then the reaction was cooled to room temperature. Water (5 mL) was added and the product was extracted with ethyl acetate (2×10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The syrup was dissolved in acetonitrile (4 mL). KI (83 mg, 3.6 mmol), K2CO3 (100 mg, 0.6 mmol) and 4-butylpiperidine (83 μl, 0.5 mmol) were added and the reaction mixture was shaken at 60° C. for 16 h. Water (5 mL) was added and the product was extracted with ethyl acetate (2×10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: 20% methanol in ethyl acetate) to yield the title compound. Yield: 24.8 mg, 11.3%. HPLC-MS: M+1+=359.5 (UV/MS(%)=90/78). 1H NMR (400 MHz, CDCl3): δ=0.89 (3H, t), 1.12-1.34 (9H, m), 1.67 (2H, broad d), 1.85 (2H, quin.), 1.93 (2H, broad t), 2.39 (2H, t), 2.59 (2H, dd), 2.83 (2H, t), 2.90 (2H, broad d), 3.76 (3H, s), 3.94 (2H, t), 6.70 (1H, d), 6.74 (1H, dd), 7.01 (1H, d). 13C NMR (CDCl3): δ 14.3, 23.0, 25.0, 26.1, 29.2, 32.1, 32.5 (2C), 35.9, 36.4, 40.8, 54.3 (2C), 55.8, 56.3, 112.2, 114.2, 116.2, 128.3, 133.4, 155.4, 169.9
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23]CC)=[O:22].[O-]CC.[Na+]>C(O)C>[CH2:26]([C:19]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][C:12]([F:14])([F:13])[F:15])=[O:9])=[CH:16][CH:17]=2)[N:2]=[N:3][C:20]=1[C:21]([OH:23])=[O:22])[CH2:27][CH3:28]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-azido-N-(2,2,2-trifluoroethyl)benzamide (0.98 g) obtained in Example 46a) and ethyl 3-keto-n-hexanoate (0.77 ml) in ethanol (20 ml) was added 20% sodium ethoxide in ethanol solution (1.85 ml) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-brown amorphous solid (1.4 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[C:5]([C:14]#[N:15])=[C:4]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:3]=1[C:25]#[N:26].[H-].[Na+].C(#N)C.O.[CH:33]1(O)[CH2:36]C[CH2:34]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH:12]2[CH2:36][CH2:33][CH2:34]2)=[O:10])[C:5]([C:14]#[N:15])=[C:4]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:3]=1[C:25]#[N:26]
Reactant: COC(=O)C(C)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C(=O)OC1CCC1)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
Methyl 2-[6-amino-4-(1,3-benzodioxol-5-yl)-3,5-dicyano-2-pyridinyl]propionate (from Example 6) (100 mg, 0.29 mmol) in cyclobutanol (5 ml) is heated under reflux with a catalytic amount of sodium hydride for 2.5 hours. The product is isolated by RP-HPLC (Kromasil column 250 * 20 mm, C18, 10 μm; acetonitrile/water gradient: 3 minutes 10%, then within 30 minutes to 80%, flow rate: 25 ml*min−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36]>>[ClH:23].[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][CH2:25][CH2:24][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1
Reactant: ClCCCCOc1ccc(Cl)cc1Cl
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)CC2
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCCCOc3ccc(Cl)cc3Cl)C1)CC2
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-dimethyoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-4-(2,4-dichlorophenoxy)-butane analogously to Example 1.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15]1([C:25](Cl)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:26])=[CH:29]1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(c1cccc2ccccc12)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-naphthalen-1-yl-methanone was prepared from phenanthridine, 1-naphthoyl chloride, and indole according to GP 2. Yield, 2%. (+)-ESI-MS: m/z=451 [M+H]+, 334 [M-indole+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1OCC(C)=C.[CH3:14][CH2:15][CH2:16]CCC.[CH:20]([OH:22])=O.O>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[C:20]2[O:22][C:15]([CH3:16])([CH3:14])[CH2:3][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=C(C)COc1ccc(F)cc1Br
Reactant: O=CO
Reactant: CCCCCC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)Cc2cc(F)cc(Br)c2O1
Temperature: 200 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution (1 mL) of the compound (560 mg, 2.28 mmol) of Step 1 in N-methyl-2-pyrrolidinone was irradiated with a microwave in a tightly-sealed container, and stirred at 200° C. for 1 hour. To the reaction solution, ethyl acetate and hexane were added. After washing with water and saturated brine, the resultant was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography. To the resulting compound (368 mg, 1.50 mmol), formic acid (2 mL) and water (0.2 mL) were added, and stirred at 100° C. overnight. The reaction solution was diluted with ethyl acetate, and after washed with water and saturated brine, the resultant was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][CH2:13]O)([O-:3])=[O:2].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:13][CH2:12][CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1NCCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1NCCCCl
Reaction time: 6 h

Procedure:
To a stirred mixture of 39.2 parts of 3-(2-nitrophenyl)amino-1-propanol and 225 parts of trichloromethane are added dropwise 35.7 parts of sulfinyl chloride (exothermic reaction: temperature rises to 45° C.) Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated, yielding N-(3-chloropropyl)-2-nitrobenzenamine as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14]C)[CH:8]=2)=[O:4].[H-].[Na+].I[CH3:19].O>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(O)cc2n1C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
To a solution of 6-methoxy-1H-indole-2-carboxylic acid methyl ester (11.57 g, 56.38 mmol) in N,N-dimethylformamide (DMF) (100 mL) was added 60% sodium hydride in oil (2.93 g, 73.29 mmol) under ice cooling. After the mixture was stirred for 15 minutes, iodomethane (3.86 mL, 62.02 mmol) was added and the mixture was stirred at the same temperature for 1 hour. To the mixture were added water and diethyl ether (Et2O), and then resulting precipitate was collected by filtration. The white precipitate was dissolved in dichloromethane (200 mL), and to the solution was added dropwise boron tribromide dichloromethane solution (100 mL) while ice cooling under an argon atmosphere. The reaction mixture was stirred at the same temperature for 1 hour, and then quenched with methanol (MeOH). The solvent was evaporated in vacuo, and water was added to the residue. The aqueous mixture was extracted with ethyl acetate (AcOEt). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 10.19 g of the title compound as a brown powder.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][CH:15]=2)[CH:12]=1.[I:16]I>O.C(O)C>[I:16][C:15]1[N:14]=[CH:13][N:11]2[CH:12]=[C:7]([CH3:6])[CH:8]=[CH:9][C:10]=12
Reactant: II
Reactant: Cc1ccc2cncn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(I)ncn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
In a round-bottomed flask, sodium bicarbonate (215 mg, 2.56 mmol) was suspended in water (0.6 ml) and ethanol (1.2 ml). 6-methyl-imidazo[1,5-a]pyridine (90 mg, 0.68 mmol) was added followed by iodine (242 mg, 0.95 mmol). The dark brown suspension was stirred at room temperature overnight then quenched with 10% Na2S2O3-solution and extracted with EtOAc (2×). The organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to provide 99 mg (56%) of 1-iodo-6-methyl-imidazo[1,5-a]pyridine as a light brown solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.11 (s, 1H), 7.73 (s, 1H), 7.24 (d, J=9.4 Hz, 1H), 6.67 (d, J=9.1 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([CH2:12][CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.[NH:21]([CH2:23][CH2:24][OH:25])[NH2:22].C(O)(=O)C>C(O)C.C(OCC)C>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([CH2:12][C:13]2[C:17]([CH3:18])=[N:22][N:21]([CH2:23][CH2:24][OH:25])[C:14]=2[CH3:15])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2
Reactant: COc1c(C)cc(CC(C(C)=O)C(C)=O)c2c1CCC2
Reactant: NNCCO
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1c(C)cc(Cc2c(C)nn(CCO)c2C)c2c1CCC2
Temperature: 70 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
To a stirred solution of 3-(7-Methoxy-6-methyl-indan-4-ylmethyl)-pentane-2,4-dione (1.0 gm 0.0036 mole) in Ethanol (15 ml), a solution of 2-Hydrazino-ethanol (0.33 gm, 0.0043 mole) in Ethanol (5 ml) was added at 25-30° C. and reaction mixture was heated to 70° C. for an hour. The Acetic acid (2 ml) was added. Further the reaction mixture was stirred at 70° C. for 3 hours. Ethanol was distilled under vacuum to give a residue which was partitioned between Ethyl acetate (50 ml) and water (25 ml). Ethyl acetate was distilled under vacuum to give a crude product The crude product was solidified after stirring in Diethyl ether (10 ml). The solid was filtered under vacuum and dried to give a 700 mg of desired compound as a solid.
Reaction SMILES: [F:1][C:2]([F:13])([S:9](Cl)(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(=O)([O-])O.[Na+].[OH:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O>C(#N)C>[F:1][C:2]([F:13])([S:9]([O:19][N:20]1[C:24](=[O:25])[C:23]2[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]1=[O:30])(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6]
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)CCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)C(F)(F)CCO
Temperature: 0 °C
Yield: 69.7 %

Procedure:
In 100 mL of acetonitrile, 25 g of a liquid of 1,1,2,2-tetrafluoro-4-hydroxybutanesulfonyl chloride (purity: 99%, equivalent to 0.102 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 10.3 g (0.123 mol) of sodium hydrogencarbonate and 18.3 g (0.112 mol) of N-hydroxyphthalimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. With this, 26.4 g of the target compound was obtained as a pale yellow solid (yield: 57%, purity: 82%, pure content: 21.6 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][C:5]2[C:11]3([CH3:14])[CH:12]([OH:13])[C:7]([CH3:15])([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:16]=1.N1C(C)=CC=CC=1C.O([Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][C:5]2[C:11]3([CH3:14])[CH:12]([O:13][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:7]([CH3:15])([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCCCCCOc1cc2c(cc1Br)C1(C)CCCC2(C)C1O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCCCCCOc1cc2c(cc1Br)C1(C)CCCC2(C)C1O[Si](C)(C)C(C)(C)C
Temperature: 35 °C
Reaction time: 8 h

Procedure:
4.49 g of the thus-obtained (5RS,9SR,10RS)-2-bromo-3-heptyloxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocycloheptene were placed in 12 ml of CH2Cl2 under argon and treated with 2.58 ml of 2,6-lutidine followed by 3.08 ml of t-butyldimethylsilyl triflate. The mixture was stirred at 35° C. overnight and then poured on to ice. The mixture was extracted with diethyl ether, washed with 1N HCl and water, dried over Na2SO4 and evaporated. Column filtration (SiO2/hexane) gave 5.39 g of (5RS,9SR,10RS)-2-bromo-10-t-butyldimethylsilyloxy-3-heptyloxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocycloheptene as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[N:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:28][C:4]2[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=2[O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[N:34][CH:33]=1
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)nc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 86.6 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.11 g, 0.27 mmol) in dioxane (1 mL) was added 6-bromomethyl-nicotinic acid methyl ester (0.075 g, 0.32 mmol) and cesium carbonate (0.15 g, 0.47 mmol). The reaction was stirred at ambient temperature for 6 days, then concentrated. Chromatography on silica gel gave the title compound (0.13 g).
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(P([N:37]=[N+:38]=[N-:39])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:37]([CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
This compound is obtained using a protocol from the literature (D. Pagé et al J. Med. Chem, 44, 2387, 2001) starting from 23 g of the compound obtained in Step A (77.3 mmol) in the presence of diphenylphosphoryl azide and triphenylphosphine in solution in THF. After purification by chromatography over silica gel using petroleum ether and ethyl acetate as eluants, the title product is obtained in the form of an oil.