Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([CH3:15])[CH:3]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(OC(=O)C)C.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.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([CH3:15])[CH:3]=1)([CH3:26])[CH3:25]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(I)ccc1OC1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1OC1CCCCO1
Temperature: 58 °C
Yield: 98 %

Procedure:
In a flask equipped with a stirrer and a thermometer, 13.36 g of 1-iodo-4-perhydro-2H-pyrane-2-yloxy-3-methylbenzene prepared in Step 2-1, 0.24 g of dichlorobis(triphenylphosphine)palladium, 0.24 g of triphenylphosphine, 0.12 g of copper iodide (I), and 12.75 g of triethyl amine were suspended in 50 g of ethylacetate under a nitrogen atmosphere, and heated up to 58° C. under stirring. Then a solution of 6.20 g of trimethylsilylacetylene and 6.20 g of ethylacetate was added dropwise at 58 to 64° C. over 2 hours. The resulting mixture was stirred at the same temperature for 3 hours, cooled down to room temperature, and filtered. The residue was washed with ethylacetate, and the resulting filtrate was concentrated at 60° C. under a pressure of 20 Torr. The concentrate was purified through silica gel chromatography using hexane mixed with 0.1 wt % triethyl amine as an eluting solvent, to thereby obtain 11.87 g of 2-(4-(trimethylsilylethynyl)-2-methylphenoxy)perhydro-2H-pyrane at 98% yield.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)=[O:8])[CH3:2].[CH2:21](OC(C1NC2C(C=1)=CC([N+]([O-])=O)=CC=2)=O)C.C(NCCN)CC>>[CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH3:21]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CCCNCCN
Product: CCCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 85 %

Procedure:
A similar procedure as described for preparation of 77 from 5-nitro-2-indolecarboxylic acid ethyl ester (0.8 g, 3.41 mmol) and N-propylethylenediamine (2 ml) gave a brown solid (0.84 g, 85%). ESI MS: 291.13 (M+H+). 1H NMR (DMSO-d6) δ 8.68 (d, 1H), 8.04 (d, 1H), 7.55 (d, 1H), 7.37 (s, 1H), 3.35 (m, 3H), 2.68 (q, 2H), 2.49 9 (q, 2H), 1.40 (tt, 2H), 0.84 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12]O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[I:39]I.Cl>ClCCl>[I:39][CH2:12][CH2:11][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(CCO)CCc1ccccc1
Reactant: II
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(CCI)CCc1ccccc1
Yield: 210.7 %

Procedure:
5 g (28 mmol) Phenoxanol (3-Methyl-5-phenyl-pentan-1-ol) is dissolved in 200 ml dichloromethane under nitrogen and stirring. Triphenylphosphine (8.8 g, 34 mmol) and 4.2 g (53 mmol) pyridine are added at 25° C. After cooling to 0° C. iodine (8.5 g, 34 mmol) is added. After 2 h stirring at 0° C. the reaction mixture is poured on ice-cooled 1 N HCl and extracted with dichloromethane. The combined organic phases are washed with 10% Na2S2O3, sat. NaHCO3 and sat. NaCl. Drying over MgSO4 and evaporation gives 17 g of a residue which is triturated with hexane and filtered over a 5 cm Silicagel pad. The filtrate is evaporated under reduced pressure and dried under high vacuum giving 7.1 g of 7c as a colorless oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30].O>C(Cl)Cl>[C-:20]1([C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5])=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21]1.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]
Reactant: O=C(Cl)CCCCCCCCCCCBr
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCCCCCCCCCBr)[c-]1cccc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Following a general procedure for preparing 21 (Creager et al. (1994) J. Electroanal. Chem., 370: 203-211), a solution of 12-bromododecanoic acid (4.2 g, 15 mmol) in SOCl2 (50 mL) was heated at 50° C. under argon for 1 h. The excess SOCl2 was removed by water pump distillation with benzene (3×50 mL). 4.3 g (95%) of 12-bromododecanoyl chloride was obtained as a colorless oil and used in the subsequent reaction without further purification. In a 50 mL flask anhydrous AlCl3 (2.8 g, 21 mmol) was added to a stirred solution of 12-bromododecanoyl chloride (4.0 g, 13.6 mmol) in dry CH2Cl2 (30 mL) at 0° C. under argon for 20 min. Then the mixture was added dropwise over 10 min to a solution of ferrocene (2.6 g, 14 mmol) in CH2Cl2 (50 mL) at 0° C. The mixture was stirred and allowed to warm to rt. After 2 h water (30 mL) was added slowly into this mixture. Then the phases were separated, and the organic layer was washed with water (3×100 mL) and NaHCO3 (2×50 mL) and over (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:3) to afford a red oil (4.3 g, 85%). 1H NMR δ 1.28 (s, 16H), 1.64 (m, 2H), 2.63 (m, 2H), 3.29 (m, 2H), 4.19 (s, 5H), 4.48 (A2B2, J=1.5 Hz, 2H), 4.78 (A2B2, J=1.5 Hz, 2H); 13C NMR δ 25.0, 28.5, 29.0, 30.1, 30.9, 33.3, 34.5, 40.5, 70.0, 70.4, 72.9, 89.0, 205.0; FAB-MS obsd 446.0955, calcd exact mass 446.0958 (C12H31.BrFeO).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[O:25]=[C:23]1[NH:15][C:14]2[CH:13]=[CH:12][C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][C:2]=2[NH:1]1
Reactant: CCOC(=O)COc1ccc(N)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a stirred solution of ethyl 2-(3,4-diaminophenoxy)acetate (144 mg, 0.685 mmol) in dry CHCl3 (5 mL) at 0° C., pyridine (0.083 mL, 1.027 mmol) and triphosgene (203 mg, 0.685 mmol) were added and allowed to stir at room temperature for two hours. Completion of the reaction was monitored by LCMS. Solvent was removed under vacuum. Water was added to the residue. The solid which formed was filtered and dried to afford crude ethyl 2-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate (85 mg, 75% by LCMS) which was used in the next step without further purification. 1H NMR: 400 MHZ, DMSO-d6: δ 1.22 (t, J=7.20 Hz, 3H), 4.18 (q, J=7.20 Hz, 2H), 4.70 (s, 2H), 6.52 (t, J=2.40 Hz, 2H), 6.81 (d, J=9.20 Hz, 1H), 10.40 (s, 1H), 10.51 (s, 1H). LCMS: RT 1.16 min. LCMS (ES-API), m/z 237.0 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13](Cl)(Cl)Cl.C1(C)C=CC=CC=1>CCCCCCCCCCCCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][SiH3:13]
Reactant: Cl[Si](Cl)(Cl)CCCCCCCCCCCBr
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCCCCCC
Product: [SiH3]CCCCCCCCCCCBr
Temperature: 60 °C

Procedure:
Freshly cleaned slides were immersed in a solution of bromoundecyl-trichlorosilane (3% v/v) in hexadecane or toluene. The reaction was heated to 60° C. for 4-6 hours then allowed to cool to room temperature. The slides were washed with CH2Cl2 and ethanol then blown dry under a stream of argon, producing a film with an advancing water contact angle of 82±2 degrees above horizontal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
4-(3-Hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 61.6 mmol), 3-trifluoromethylphenol (19.4 g, 64.7 mmol), triphenylphosphine (1.40 g, 73.9 mmol) and tetrahydrofuran (200 ml) were mixed. While stirring the mixture at room temperature, DEAD (21.1 ml, 80.0 mmol) was added thereto dropwise and heated at reflux for 2 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=87:13) to afford the title compound as a pale yellow oil (20.5 g, yield 86%).
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:25][OH:26])[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:24])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl>C(OCC)(=O)C>[F:23][C:20]([F:22])([F:21])[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12](=[O:24])[C:11]12[C:3]2=[CH:4][C:5]3[O:9][CH2:8][O:7][C:6]=3[CH:10]=[C:2]2[O:26][CH2:25]1
Reactant: O=C1Nc2c(C(F)(F)F)cccc2C1(CO)c1cc2c(cc1O)OCO2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1Nc2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (4.10 g, 11.7 mmol) in ethyl acetate (100.0 mL) was added tributylphosphine (3.4 mL, 2.83 g, 13.9 mmol) at 0° C. followed by the solution of di-tert-butyl azodicarboxylate (3.22 g, 13.9 mmol) in ethyl acetate (50.0 mL). The reaction solution was stirred at 0° C. for 30 min followed by the addition of 10% hydrochloric acid (50.0 mL). The reaction solution was washed with 10% hydrochloric acid (2×50.0 mL), saturated ammonium chloride (3×50 mL) and brine (3×50 mL). The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by flash chromatography to afford 7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (3.59 g, 88%): mp 245-248° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.11 (dd, J=7.5, 7.5 Hz, 1H), 6.66 (s, 1H), 6.32 (s, 1H), 5.90 (d, J=3.1 Hz, 2H), 4.74 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 179.4, 156.0, 148.9, 139.7, 134.9, 128.3, 125.8, 125.7 (m), 122.9, 119.7, 112.0, 111.4 (m), 103.6, 101.9, 93.7, 80.4, 57.5; MS (ES+) m/z 350.3 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[O:15].Br[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].[Mg]>C(OCC)C.COCCOCCOC.C(Cl)Cl>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]([OH:15])[CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCBr
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Mg]
Solvent: ClCCl
Solvent: COCCOCCOC
Solvent: CCOCC
Product: C=CCCCC(O)c1ccc2c(c1)Cc1ccccc1-2
Reaction time: 0.5 h

Procedure:
2-Fluorenecarboxaldehyde (3 g) was dissolved in a mixture of anhydrous diethyl ether (30 ml) and anhydrous diglyme (5 ml) and was reacted with a grignard prepared from 5-bromopentene and magnesium, as described for example 23. The mixture was stirred for 30 min and a precipitate filtered off and washed with diethyl ether to give a white powder. The powder was dissolved in DCM and washed with saturated NH4Cl and water. Evaporation gave an oil which rapidly solidified. Column chromatography gave the title compound as a white solid. δC (CDCl3, 62.9 MHz): 25.2, 33.7, 36.9, 38.7, 74.8, 114.8, 119.8, 119.9, 122.6, 124.7, 125.1, 126.7, 126.8, 138.7, 141.2, 141.5, 143.4, 143.6 and 143.6.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH:13]=[CH2:14])=[O:8])=[O:5].[OH:15]O>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]([NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12]([CH:13]=[CH2:14])=[O:15])=[O:8])=[O:5]
Reactant: OO
Reactant: C=CSCCNC(=O)NC(=O)CCCl
Solvent: CC(=O)O
Product: C=CS(=O)CCNC(=O)NC(=O)CCCl
Reaction time: 2 h

Procedure:
4.05 g Intermediate 6 in 20 ml acetic acid was oxidised with 30 % hydrogen peroxide in the usual way. After 2 hours, the solution was evaporated and the residue stirred with ether. The solidified product was filtered off and recrystallised from ethanolpetrolether. Yield 3.1 g; Mp. 113° to 135° C.
Reaction SMILES: [CH3:1][C:2]([N+:20]([O-])=O)([CH3:19])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1>[Ni].CN(C)C=O>[NH2:20][C:2]([CH3:1])([CH3:19])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)N)cc1
Yield: 91.5 %

Procedure:
A mixture of 6-[4-(2-methyl-2-nitropropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (412.6 g), Raney nickel (100 ml) and dimethylformamide (1.5 liters) was hydrogenated under atmospheric pressure. After the absorption of hydrogen ceased, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give 6-[4-(2-amino-2-methylpropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (340.39 g).
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=O)(C)(C)C.[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([NH2:32])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18]>>[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([NH:32][C:10]([C@@H:9]3[CH2:13][C:14](=[CH2:16])[CH2:15][NH:8]3)=[O:12])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: C=C1CN[C@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=320.2.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[NH:25][C:24](=[O:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:27].[C:30]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[N:25]([CH3:30])[C:24](=[O:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:27]
Reactant: CC(C)(C)Cn1c(Cn2[nH]c(=O)c3ccccc3c2=O)cc2cnc(C#N)nc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2ccccc2c(=O)n1Cc1cc2cnc(C#N)nc2n1CC(C)(C)C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of 338 mg (1.3 mmoles) of phthalhydrazide in 20 ml of DMF, 252 mg (1.83 mmoles) of K2CO3 and 400 mg (1.30 mmoles) of 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:2) give 412 mg of desired 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 70% yield. The obtained product is treated with MeJ under the same conditionto give N-methylated compound. To a solution of 295 mg (0.76 mmoles) of 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 20 ml of DMF, 0.066 ml (1.06 mmoles) of MeJ and 168 mg (1.22 mmoles) of K2CO3 are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:4) give 238 mg of 7-(2,2-Dimethyl-propyl)-6-(3-methyl-1,4dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:44][C:45]([O:47][CH3:48])=[O:46].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]([CH2:44][C:45]([O:47][CH3:48])=[O:46])[N:18]=[N:19][N:20]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 138; 2 g, 3.4 mmol), methyl bromoacetate (0.5 ml, 5.1 mmol) and potassium carbonate (0.75 g, 0.51 mmol) were stirred in acetonitrile (20 ml) at 45° C. for 90 minutes. After this time the mixture was concentrated in vacuo and the residue partitioned between brine and ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated. The residual clear oil was chromatographed on silica gel eluting with 10, 20 and 50% ethyl acetate/iso-hexanes to yield the title compounds: isomer A (1.2 g, 54%) and isomer B (0.9 g, 40%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:23]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[CH:5]3[CH:14]([CH2:13][CH2:12][C:11]=2[CH:10]=1)[CH:15]1[C:2]([CH3:1])([C:18](=[O:19])[CH2:17][CH2:16]1)[CH2:3][CH2:4]3)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC12CCC3c4ccc(OCc5ccccc5)cc4CCC3C1CCC2=O
Temperature: 80 °C

Procedure:
A solution of 15 g (55 mmol) of estrone in DMF (110 mL) was cooled to 0° C. and 2.44 g (61 mmol) of NaH (60% in oil) were added slowly. The mixture was stirred at 0° C. under N2 for 1 h before addition of 13.2 mL (111 mmol) of benzyl bromine dropwise at 0° C. The reaction was then heated to 80° C. for 4 h. After cooling, the mixture was poured into water. The suspension was extracted by diethyl ether (5 times). The mixed organic layer were washed with 2N HCl (3 times) and brine, dried over Na2SO4 and concentrated in vacuo. Recrystallisation of the solid residue in ethanol gave 12.33 g (62%) of JAC01002 as beige solid. 1H NMR (400 MHz, CDCl3) δ 0.92 (s, 3H, CH3); 1.49-1.63 (m, 6H); 1.99-2.05 (m, 3H); 2.17 (dAB, J=18.9, 8.9 Hz, 1H); 2.23 (m, 1H); 2.40 (m, 1H); 2.51 (dAB, J=18.9, 8.9, 1H); 2.85 (m, 2H, CH26); 5.05 (s, 2H, OH2Ph); 6.74 (d, J=2.8 Hz, 1H, H4); 6.80 (dd, J=8.5, 2.8 Hz, 1H, H2); 7.21 (d, J=8.5 Hz, 1H, H1); 7.30-7.45 (m, 5H); Acq. Mass (FAB+) calcd 360.2089, obsd 360.21675 (M+).
Reaction SMILES: [F:1]C1C=CC=CC=1C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[N:19]=1>>[F:11][C:12]1[C:17]([F:1])=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[N:19]=1
Reactant: Fc1ccccc1-c1nc2ccncc2[nH]1
Reactant: O=C(O)c1ccccc1F
Product: Fc1cccc(-c2nc3ccncc3[nH]2)c1F

Procedure:
Following the above taught procedure and substituting 2-fluorobenzoic acid in place of 2,3-difluorobenzoic acid, the compound 2-(2-fluorophenyl)-3H-imidazo[4,5-c]pyridine can be prepared.
Reaction SMILES: C1CO[C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=2[CH2:11][C@H:10]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:21][C:14]1[CH:15]=[CH:16][C:17]2[C@@H:18]3[C@H:9]([C@H:6]4[C@@:4]([CH2:20][CH2:19]3)([CH3:5])[C:3](=[O:2])[CH:8]=[CH:7]4)[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:11][C:12]=2[CH:13]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Yield: 98.7 %

Procedure:
A solution of 36.12 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol in 958 ml of acetone and 111 ml of water is stirred for 2 hours at room temperature with 2.76 g of para-toluenesulfonic acid. Then, it is concentrated by evaporation in a vacuum to 1/3 of the volume, taken up with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. 31.7 g of 3-hydroxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one is obtained as crystals with a melting point of 194°-196° C.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([N:10]2[C:14]3=[CH:15][C:16]4[O:20][CH:19]=[N:18][C:17]=4[C:21]([F:22])=[C:13]3[N:12]([C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])C2=O)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[Si](C)(C)[O-].[K+]>C1COCC1>[CH2:1]([C:4]1([S:7]([NH:10][C:14]2[C:13]([NH:12][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])=[C:21]([F:22])[C:17]3[N:18]=[CH:19][O:20][C:16]=3[CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4ncoc4cc32)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)Nc2cc3ocnc3c(F)c2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (120 mg, 0.23 mmol) in THF (10 mL) was added potassium trimethylsilanolate (48 mg, 0.35 mmol). The reaction was stirred at room temperature for 1 h and quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with EA (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (100 mg, 87.0% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.42 (m, 1H), 7.31-7.25 (m, 1H), 6.80 (s, 1H), 6.43-6.35 (m, 1H), 6.21 (s, 1H), 5.85-5.70 (m, 1H), 5.22-5.14 (m, 2H), 2.83 (d, 2H), 1.28-1.20 (m, 2H), 0.87-0.80 (m, 2H).