Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([N:67]5[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]5)=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][O:36]C3CCCCO3)[CH:28]=2)[N:26]=1)([CH3:21])([CH3:20])[CH3:19]>CO.O>[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([N:67]5[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]5)=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][OH:36])[CH:28]=2)[N:26]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cccc(OCCO)c2)n1
Temperature: 40 °C
Reaction time: 19 h

Procedure:
Pyridinium p-toluenesulfonate (362 mg, 1.44 mmol) was added to a solution of Intermediate 39c (360 mg, 0.48 mmol) in MeOH (5 mL). The solution was stirred at 40° C. for 19 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-7.5% [2M NH3 in MeOH] in DCM, to give the title compound as a white powder after freeze-drying (218 mg, 68%). LCMS (Method 5): Rt 4.22 min, m/z 665 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.60-1.63 (2H, m), 1.70-1.75 (4H, m), 1.86-1.92 (2H, m), 2.01-2.06 (1H, m), 2.10-2.16 (1H, m), 3.14 (4H, t, J 5.2), 3.71 (2H, q, J 5.1), 4.03 (2H, t, J 5.0), 4.79-4.82 (1H, m), 4.87 (1H, t, J 5.5), 5.54 (1H, t, J 4.3), 6.33 (1H, s), 6.96 (1H, m), 7.11-7.22 (4H, m), 7.34-7.46 (5H, m), 7.61-7.64 (2H, m), 8.11 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[I:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:28]([C:25]3[CH:26]=[CH:27][C:22]([I:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(I)cc1

Procedure:
Starting with (R)-(5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (example 1-2, method B, 1st step) and 4-iodobenzenesulfonyl chloride, using the method analogous to the one used for example 1-1, method A, 4th step, (R)-[5-(4-iodo-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester was obtained. MS cald. for C22H26INO5S 543, obsd. 544 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH3:21][C:22]1([CH3:45])[CH2:27][CH2:26][C:25]2[CH:28]=[C:29]([CH2:32][CH2:33]C3C=C(C)C=CC=3S([O-])(=O)=O)[CH:30]=[CH:31][C:24]=2[O:23]1>O>[CH3:21][C:22]1([CH3:45])[CH2:27][CH2:26][C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][O:1][C:2]3[CH:3]=[C:4]([NH:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=3)[CH:30]=[CH:31][C:24]=2[O:23]1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCc2ccc3c(c2)CCC(C)(C)O3)c1
Reactant: CN(C)C(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Nc1cccc(OCCc2ccc3c(c2)CCC(C)(C)O3)c1
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
1.8 g of 1-(3-hydroxyphenyl)-3,3-dimethylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.4 g of 60% sodium hydride was added thereto. After the mixture was stirred for 15 minutes, 3.6 g of 3-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)ethyl]-p-toluene sulfonate was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into iced water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous sodium sulfate and ethyl acetate was distilled off. The residue was purified by silica gel column chromatography using n-hexane/ethyl acetate (1/1) as a developer to obtain 2.4 g of Compound No. 94 shown in Table 5.
Reaction SMILES: Br[CH:2]([CH:7]([OH:10])[CH2:8][Br:9])[C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[Na+]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[Br:9][CH2:8][C@@H:7]([OH:10])[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)C(O)CBr
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](O)CBr
Reaction time: 2 h

Procedure:
An argon purged solution of the dibromide obtained in step (b) above (20.8 g, 75.4 mM) and anhydrous sodium acetate (NaOAc) (21.0 g) in ethyl acetate (370 ml) and glacial acetic acid (37 ml) was treated with 5% Pd/C (1.30 g) and the black suspension stirred under one atmosphere of H2 while monitoring uptake (22.4 l/mole). After 2.0 hours H2 uptake was complete, the mixture was filtered through Celite, the filtrate washed with saturated NaHCO3 and brine and then dried over anhydrous MgSO4 and evaporated to give the crude bromoester title product as a brown oil. The crude oil was combined with another batch (starting from 36.77 g of the dibromide) and vacuum distilled to give 25.771 g (61.3%) of the pure bromoester title product as a clear oil with b.p.=79°-80° C. (1.0 mm Hg) and with consistent C13NMR spectral data. TLC (1:1) ethyl acetatehexane, Rf=0.44, PMA.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[N:13][CH:12]=[C:11]2O.C(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[N:13][CH:12]=1
Reactant: COc1cc2nncc(O)c2cc1OC
Reactant: O=P(Br)(Br)Br
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2nncc(Br)c2cc1OC
Temperature: 65 °C
Reaction time: 18 h

Procedure:
Phosphorus oxybromide (125 g, 0.436 mol) was added to a suspension of 6,7-dimethoxycinnolin-4-ol (65 g, 0.32 mol) in chloroform (550 mL, 6.9 mol). The reaction mixture was stirred at 65° C. for 18 hours. Formation of a fine yellow solid was observed. The reaction mixture was poured onto crushed ice (200 g), and the pH was adjusted to 6-7 with sodium acetate (285 g) and sat. NaHCO3. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide a light tan oil. DCM (40 mL) and hexanes (250 mL) were added, and the resulting solid was filtered to provide 4-bromo-6,7-dimethoxycinnoline as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][OH:24])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1OCC(=O)N(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CO
Product: OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of (6RS,7SR)-4-benzyl-7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-(3,4-dichlorophenyl)-1,4-oxazepan-3-one (3.11 g) in THF (20 mL) was added 1 M THF solution (13.8 mL) of borane-THF complex at 0° C., and the mixture was stirred at 60° C. for 2 hr. To the reaction mixture was added methanol, and the solvent was evaporated under reduced pressure. To the residue was added 6 N hydrochloric acid (8 mL), and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was basified with 8 N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.22 g).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[N:21]=[C:20]([SH:22])[NH:19][N:18]=1>>[NH2:16][C:17]1[NH:18][N:19]=[C:20]([S:22][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:15])[C:6]=2[CH2:12][CH2:13][CH3:14])[N:21]=1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: Nc1n[nH]c(S)n1
Product: CCCc1c(CSc2n[nH]c(N)n2)ccc(C(C)=O)c1O
Yield: 61.7 %

Procedure:
Using 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 0.18 g of 3-amino-5-mercapto-1,2,4-triazole as starting materials, 0.25 g of 4'-[[(5-amino-1,2,4-triazol-3-yl]thio]methyl]-2'-hydroxy -3'-propylacetophenone was obtained in a manner similar to Example 25.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:28])([F:27])[O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.CCOC(C)=O>CCOCC>[F:7][C:8]([F:27])([F:28])[O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Cc2ccc(OC(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1ccc(Cc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
LiAlH4 (55 mg, 1.45 mmol) was added to a solution of ester 94 (203 mg, 0.65 mmol) in ether (5 mL) and the mixture was stirred at room temperature for 3 h, then EtOAc (150 mL) was added. The organic layer was washed with water, the aqueous layer was re-extracted with EtOAc (100 mL), and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give {4-[4-(trifluoromethoxy)benzyl]phenyl}methanol (95) (185 mg, quant.) as a white solid: mp (EtOAc/hexane) 60-61° C.; 1H NMR (CDCl3) δ 7.32-7.27 (m, 2H), 7.20-7.14 (m, 4H), 7.13-7.09 (m, 2H), 4.67 (s, 2H), 3.98 (s, 2H); HREIMS calcd for C15H13F3O2 m/z (M+) 282.0868, found 282.0866.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10](=[O:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([OH:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(3S)-3-tert-Butoxycarbonylamino-1-chloro-5-methyl-2-hexanone (263.8 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.0001 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-5-methylhexane (255.8 mg; yield: 96.4%). As a result of HPLC analysis, the production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was 7.7:1. The results of elementary analysis were as follows.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[C:21]2[N:20]=[C:18]([NH2:19])[NH:17][C:15](=[O:16])[C:14]=2[N:13]=[CH:12]1.C[Si](Cl)(C)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].[NH4+].[OH-]>N1C=CC=CC=1.O>[C:27]([NH:19][C:18]1[NH:17][C:15](=[O:16])[C:14]2[N:13]=[CH:12][N:11]([C:21]=2[N:20]=1)[C@@H:4]1[O:5][C@H:6]([CH2:9][OH:10])[C@@H:7]([OH:8])[C@H:3]1[O:2][CH3:1])(=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C(=O)Cl
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Reaction time: 0.33 h

Procedure:
2'-O-methylguanosine (3.5 g) in pyridine (100 ml) was treated with trimethylsilyl chloride (9 ml, 6 eq) and isobutyryl chloride (6.2 ml) at RT for 4 hr. The reaction mixture was cooled in an ice bath, H2O (20 ml) was added and stirring continued for an additional 20 min. NH4OH (20 ml) was added and after stirring for 30 min the reaction mixture was evaporated. The residue was triturated with H2O, filtered and the filtrate evaporated and purified by silica gel chromatography as per the procedure of Example 4 to yield the product as an off white solid (1.5 g). 1H NMR (DMSO-d6) δ 1.1 [d, 6, CH(CH3)2 ], 2.77 [m, 1, CH(CH3)2 ], 3.33-3.6 (m, 5, OCH3, H-5'), 3.93 (m, 1, H-4'), 4.22 (m, 1), 4.3 (m, 1), 5.1 (t, 1, 5'-OH), 5.28 (d, 1, 3'-OH), 5.9 (d, 1, H-1'), 8.28 (s, 1, H-8) and 11.9 (br s, 1, NH).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]([O:14]CC)=[CH2:13])=[CH:7][N:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CC(OC)(C)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:14])[CH3:13])=[CH:7][N:6]=1)=[O:4]
Reactant: C=C(OCC)c1cnc(C(=O)OC)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ncc(C(C)=O)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 3-chloro-5-(1-ethoxy-vinyl)-pyridine-2-carboxylic acid methyl ester (359 mg, 1.485 mmol) in THF (3.6 ml) was added para-toluenesulfonic acid monohydrate (565 mg, 2.97 mmol) and the mixture was stirred for 1 h. The reaction mixture was diluted with TBME and sat. aq. NaHCO3, the layers were separated and the aq. Phase was extracted with TBME. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc 9:1 to 6/1) to provide the title compound as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][O:17][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)CO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: CC(C)(C)COS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
Add 4-bromobenzenesulfonyl chloride (2.20 g, 8.61 mmol) and pyridine (30 mL) to a round bottom flask. At ambient temperature, with stirring, add neopentyl alcohol (1.39 mL, 12.91 mmol). After stirring the reaction overnight at ambient temperature quench the reaction with saturated aqueous sodium bicarbonate and extract it with ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, 0.05 N aqueous hydrochloric acid and brine, then dry (sodium sulfate), and concentrate in vacuo. Purify the resulting-material on a flash column (silica gel; 30%-50% gradient of CH2Cl2 in hexanes) to provide 2.24 g of 4-bromo-benzenesulfonic acid 2,2-dimethyl-propyl ester (85%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.O>C(#N)C.[Cu](Br)Br>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCBr)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Br[Cu]Br
Solvent: CC#N
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2=O
Reaction time: 8 h

Procedure:
17.0 g of copper(II) bromide are added at 80° C. to 27.8 g of 7α-(5-bromopentyl)-11β-fluorooestr-4-ene-3,17-dione in 190 ml of acetonitrile. After 8 hours, the reaction mixture is stirred into water, extracted 3 times with ethyl acetate, washed twice with ammonium chloride, with sodium hydrogencarbonate and sodium chloride, dried and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 20.4 g of 7α-(5-bromo-pentyl)-11β-fluoro-3-hydroxyestra-1,3,5(10)-trien-17-one are obtained as colourless crystals of melting point 178° C.
Reaction SMILES: CO.O.[CH3:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)=[CH:8][CH:7]=1>CO.O.[Fe]>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[NH2:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: COc1ccc(COc2cccc(N)c2)cc1
Yield: 99.2 %

Procedure:
Fe (5.6 g, 100.28 mmol) was mixed with methanol:H2O (15 ml:3 ml) and refluxed for 30 minutes. After the temperature is dropped to room temperature, 1-(4-methoxybenzyloxy)-3-nitrobenzene (1.3 g, 5.01 mmol) dissolved in 6 ml of methanol:H2O (5:1) was added and then refluxed for 15 hours. Fe was removed using cellite, then the reaction mixture was washed using methanol and concentrated under vacuum to remove the solvent. After extraction with 100 ml of saturated ammonium chloride+150 ml of dichloromethane, the organic layer was washed with water. The organic solvent was concentrated under vacuum to obtain the title compound (1.14 g, 99%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].O>O1CCCC1>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)=[O:23]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCC(Cl)(Cl)Cl)C1
Yield: 46.2 %

Procedure:
To a solution of tert-butyl 3-aminopiperidine-1-carboxylate (1.00 g, 4.99 mmol) and pyridine (489 ml, 5.99 mmol) in tetrahydrofuran (16 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.829 ml, 5.99 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was introduced to water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 867 mg (46.2%) of the desired product as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:6].[CH3:24][N:25]([CH3:36])[C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[NH:29][C:30](=[O:32])[CH3:31].C1(C)C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH3:23][N:2]([CH3:1])[C:3]1[CH:19]=[C:18]([N:20]([CH3:21])[CH3:22])[CH:17]=[CH:16][C:4]=1[C:5]1([C:33]2[CH:34]=[CH:35][C:26]([N:25]([CH3:36])[CH3:24])=[CH:27][C:28]=2[NH:29][C:30](=[O:32])[CH3:31])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[O:6]1
Reactant: CC(=O)Nc1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)c(N(C)C)c1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N(C)C)ccc1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
In a manner similar to that of part B of Example 3 condensation of 2-(2,4-bis(dimethylamino)benzoyl)benzoic acid (2.4 g.) and m-(dimethylamino)acetanilide (1.42 g.) and recrystallization of part of the product from a mixture of toluene, ligroin and hexane and part from a mixture of ethyl acetate and hexane afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-acetamido-4-(dimethylamino)phenyl)phthalide (I: X = Y4 = (CH3)2N, Y2 = CH3CONH, Z4 = Z5 = Z6 = Z7 = H) (m.p. 97°-136° C.).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[CH:29]=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:41])=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[H][H]>CO.CCOC(C)=O.[Pd]>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[CH:29]=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:41])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(Cn2cncc2CN2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CN2CCN(c3cccc4ccc(O)cc34)C(=O)C2)cc1F
Reaction time: 8 h

Procedure:
To a solution of the benzyl ether from Step F (1.563 g, 2.85 mmol) in 25 mL of 1:1 MeOH/EtOAc was added trifluoroacetic acid (1.0 mL) and 10% palladium on carbon (900 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 8 hours, the solution was filtered through celite, and the filter pad was rinsed with 1:1 MeOH/THF. Concentration in vacuo provided the titled product as a white foam which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCCC1[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.Br[C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:14]1[CH:15]=[CH:16][C:17]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:18][CH:19]=1)[OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: O=C(c1ccccc1)C(CCOCc1ccccc1)c1ccccc1
Product: OC(c1ccccc1)(c1ccc(OC2CCCCO2)cc1)C(CCOCc1ccccc1)c1ccccc1

Procedure:
The compound is prepared from the evaporation residue obtained in step (a) and 38.6 g of tetrahydropyran-2-yl ether-protected 4-bromophenol according to the procedure described in Example 1(b).
Reaction SMILES: C(C(CC)(CC)C[CH:5](P(O)(O)=O)[C:6]([O-:8])=[O:7])C.[H-].[Na+].[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=O.[C:31]1(C)C=CC=C[CH:32]=1>C1COCC1>[CH2:31]([O:8][C:6](=[O:7])/[CH:5]=[CH:29]/[C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=1)[CH3:32]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: Cc1ccccc1
Reactant: CCC(CC)(CC)CC(C(=O)[O-])P(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A solution of triethyl-2-phosphonobutyrate (26.6 g, 118.7 mmol) in dry toluen (250 ml) was cooled on ice and added sodium hydride (60% in oil, 3.3 g, 134.6 mmol). After stirring at 0° C. for 20 min. a solution of quinolinecarboxaldehyde (12.5 g, 79.5 mmol) in dry THF (30 mL) was added. The mixture was slowly warmed to room temperature, and stirring continued for 24 h. The reaction mixture was quenched with ethanol and added water. The aqueous phase was extracted with dichloro methane (×2). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was submitted to flash chromatography, eluting with heptane graduated to heptane/ethyl acetate (4:1), to give 12.5 g (70%) of (E)-3-quinolin-2-yl-acrylic acid ethyl ester.