Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:32][CH2:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: COc1ccccc1CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccccc1CCNc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 140 °C
Yield: 16.2 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.64 mmol), 2-[2-(methyloxy)phenyl]ethanamine (500 mg, 3.31 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 4 hours at 140° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC (gradient: 10% CH3CN/H2O to 30% CH3CN/H2O) to afford the title compound (100 mg) as a yellow solid. LC-MS (ES) m/z=376 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.81-2.84 (m, 2H), 3.52 (m, 2H), 3.74 (s, 3H), 5.37 (s, 2H), 6.01 (s, 2H), 6.28 (s, 1H), 6.76-6.86 (m, 4H), 7.22 (t, J=8.4 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([NH:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)CCC.[ClH:41].O1CCOCC1>O1CCOCC1>[ClH:41].[O:34]1[C:33]2[CH:38]=[CH:39][C:30]([CH2:29][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[C:21]([NH:26][CH3:27])[CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:28])[CH2:10][CH2:9]3)=[CH:31][C:32]=2[O:37][CH2:36][CH2:35]1
Reactant: CCCCOC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(NC)cccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 60 mg of tent-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(N-methylamino)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature for 3 hours. The resulting solid was filtered to give 30 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-(N-methylamino)quinolin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[CH:30]=[C:29]([CH3:31])[O:28][N:27]=1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:25][C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(CCl)no1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1Cc1cc(C)on1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of Example 244A (275 mg, 0.84 mmol) in DMF at 0° C. was treated with 60% NaH in mineral oil (40 mg, 1.03 mmol). After the gas evolution subsided, the reaction mixture was allowed to stir for 30 min and then treated with commercially available 3-(chloromethyl)-5-methylisoxazole (111 mg, 0.847 mmol). The resulting mixture was stirred at room temperature for 18 hr, poured into brine and extracted with EtOAc. The organics were combined and washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography over silica gel using 20% EtOAc in hexane to afford the title compound (165 mg, 37% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.32 (s, 9H), 2.38 (s, 3H), 3.77 (s, 3H), 5.39 (s, 2H), 6.23 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.45 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (d, J=3.1 Hz, 1H). MS (DCI) m/z 420 (M+H)+. Elemental analysis calculated for C20H22ClN3O3S: C, 57.20; H, 5.28; N, 10.01. Found: C, 57.16; H, 5.42; N, 9.75.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=1)=[O:24]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:30]3[CH:31]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:27]=[N:28][CH:29]=3)[CH2:33][CH2:34]2)=[O:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1cncc(C2CCNCC2)c1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cncc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 170 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2-methyl-N-[5-(4-piperidinyl)-3-pyridinyl]propanamide according to the procedures described in Scheme 14: 1H NMR (400 MHz, CDCl3) δ 8.47–8.42 (m, 1 H), 8.21–8.16 (m, 1 H), 8.09 (s, 1 H), 7.59 (s, 1 H), 7.35–7.20 (m, 10 H), 6.87 (s, 1 H), 4.91 (s, 1 H), 3.46–3.36 (m, 2 H), 3.01–2.92 (m, 2 H), 2.62–2.47 (m, 2 H), 2.47–2.37 (m, 2 H), 2.11–1.94 (m, 4 H), 1.86–1.59 (m, 4 H), 1.25 (d, 6 H, J=7.2 Hz); ESMS m/e: 499.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][S:30]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=3)(=[O:32])=[O:31])=[C:19]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C4CCCC4)c3)c2c1C

Procedure:
Using 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.289 g, 0.641 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.717 g, 3.03 mmol) the title compound was prepared according to the procedure in Example 1, step 9. Purification on Dynamax C18 eluting with 100% CH3CN (0.1% TFA added) gave 0.25 g (60%) of the title compound as a yellow solid, mp >225° C.; 1H NMR (DMSO-d6) δ 1.31-1.36 (m, 2 H), 1.49-1.59 (m, 5 H), 1.61-1.63 (m, 3 H), 1.78-1.82 (m, 1 H), 2.44 (s, 3 H), 3.04-3.10 (m, 1 H), 7.25-7.31 (m, 3 H), 7.34-7.37 (m, 3 H), 7.50 (t, 1 H), 7.66 (t, 1 H), 8.02 (d, 1 H), 8.21 (d, 1 H). IR (KBr): 3425, 2900, 1650, 1400 and 1175 cm-1. mass spectrum (-ESI), m/z 649/651 (M-H). Anal. Calcd. for C32H27BrO6S2.0.6H2O: C, 58.02; H, 4.29 N, 0.00. Found: C, 57.98; H, 4.35 N, 0.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:21][C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: O=Cc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A mixture of 5,6-dimethoxy-indan-1-one (10 g), pyridine-4-carboxaldehyde (7.8 g), p-toluenesulphonic acid (13.8 g) in toluene (120 ml) was refluxed azeotropically for 6 hours. The reaction mixture was cooled to room temperature and filtered. The wet solid so obtained was stirred with 10% aqueous sodium carbonate solution. The solid was filtered, washed with acetone and then dried to get the title compound (13.2 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3]C1.C[OH:41]>>[Cl:39][C:36]1[CH:35]=[N:34][C:33]([O:32][CH2:31][CH2:30][O:29][C:11]2[C:10]([C:8]3[CH:7]=[CH:6][C:5]([OH:1])=[C:4]([OH:3])[CH:9]=3)=[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH2:26][OH:41])=[CH:21][N:20]=3)(=[O:17])=[O:18])[N:13]([CH3:28])[N:12]=2)=[N:38][CH:37]=1
Reactant: CO
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Product: CC(CO)c1ccc(S(=O)(=O)Nc2c(-c3ccc(O)c(O)c3)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS7-H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron Shaker™ with 1″ throw. 2 mls of this inoculum medium was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-isopropyl-2-pyridinesulfonamide (Example 103) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Br:11]N1C(=O)CCC1=O>>[Br:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:2])[O:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccccc21
Product: O=C1OC(Br)c2ccccc21

Procedure:
A benzoic acid derivative of formula 1 is reacted with formaldehyde under acidic conditions to yield a phthalide derivative of formula 2. ##STR4## The phthalide derivative is then brominated with any suitable brominating agent, e.g. N-bromosuccinimide to yield an unstable bromophthalide derivative, 3, which is readily reacted with water to a phthalaldehydic acid derivative, 4. ##STR5## The phthalaldehydic acid derivative may then be oxidized to the desired phthalic anhydride derivative, 5, in good yield using a suitable oxidizing agent such as manganese dioxide. ##STR6##
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a flask was charged with tetrakis-(triphenylphosphine)-palladium (46 mg, 0.040 mmol) under nitrogen. A solution of 6-(1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (130 mg, 0.40 mmol) in DMF (5 mL) was added. The system was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (0.14 mL, 0.42 mmol) was added. The temperature was increased to 100° C. and stirred for 2 hrs. Then the reaction mixture was cooled to room temperature, 3N HCl was added and the mixture was stirred for additional 4 hrs. Water was added and the mixture was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in CH2Cl2) to afford 120 mg (yield: 90) of title compound. LCMS (method B): [MH]+=335, tR=2.41 min.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.S(=O)(=O)(O)O.[N+:15]([C:18]1[C:19]([CH3:30])=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)C(O)=O)([O-:17])=[O:16].[N-:31]=[N+]=[N-].[Na+]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[N+:15]([C:18]1[C:19]([CH3:30])=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[NH2:31])([O-:17])=[O:16]
Reactant: Cc1c(C(=O)O)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1c(N)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 45 °C
Yield: 86 %

Procedure:
Chloroform (38 ml.) was added carefully to a stirred mixture of oleum (16.9 ml.: 20% free sulphur trioxide) and concentrated sulphuric acid (3.8 ml.) followed by 3,5-dinitro-2-methylbenzoic acid (10.0 g.). The mixture was warmed to 45°C. and sodium azide (3.28 g.) was added in small portions over 20 minutes, the temperature of the reaction mixture being kept between 45° and 50°C. by means of intermittent cooling. After the addition was complete, the mixture was stirred and heated under reflux for 1 hour on the steam bath and then the chloroform was removed by decantation and the residue was poured into ice-water (300 ml.). The yellow precipitate was filtered off, washed with water and dried, to give crude 3,5-dinitro-2-methylaniline (8.8 g.), m.p. 169°-171°C. The crude product was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and then with water and the solvent was removed in vacuo. Trituration with petroleum ether (b.p. 40°-60°C.) gave 3,5-dinitro-2-methylaniline (7.5 g.), m.p. 172.5°-174.5°C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[F:19][C:20]1[C:25]([F:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38]>>[F:19][C:20]1[C:25]([F:26])=[C:24]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[C:5]3[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=3[N:7]=2)[CH:23]=[CH:22][C:21]=1[NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1F
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)c(F)c1F
Yield: 4.2 %

Procedure:
Method as example 47 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-ethylurea as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The crude material was purified first by Flash Chromatography using a gradient of 0-40% DCM/MeOH, then prep. HPLC at low pH yielding the title compound (8.7 mg, 0.01 mmol, 4.2%).
Reaction SMILES: N12CCN(CC1)CC2.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[NH2:21][C@H:22]1[C@@H:34]2[C:35](=[O:38])[O:36][CH2:37][C@H:33]2[C@H:32]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][Si](C(C)(C)C)(C)C)=[C:41]([O:55][CH3:56])[CH:40]=2)[C:31]2[C:23]1=[CH:24][C:25]1[O:29][CH2:28][O:27][C:26]=1[CH:30]=2>ClCCl>[OH:47][C:42]1[C:43]([O:45][CH3:46])=[CH:44][C:39]([C@@H:32]2[C:31]3[C:23](=[CH:24][C:25]4[O:29][CH2:28][O:27][C:26]=4[CH:30]=3)[C@@H:22]([NH:21][C:16](=[O:18])[C:15]3[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=3)[C@@H:34]3[C:35](=[O:38])[O:36][CH2:37][C@@H:33]23)=[CH:40][C:41]=1[O:55][CH3:56]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O[Si](C)(C)C(C)(C)C
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](NC(=O)c3ccc([N+](=O)[O-])cc3)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
0.4 mmol of 1,4-diazabicyclo[2.2.2]octane and then 0.78 mmol of para-nitrobenzoic acid are added to a solution of 0.6 mmol of the compound obtained in Step 1 in 10 ml of anhydrous dichloromethane. After 7 hours at ambient temperature, the reaction mixture is evaporated and the residue is chromatographed. The isolated product is then dissolved in 50 ml of methanol and Dowex 50X2-200 resin is added. After stirring for 15 hours at ambient temperature, the reaction mixture is filtered and then concentrated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([CH3:15])=[CH:8][CH2:9][CH2:10][C:11](Cl)([CH3:13])[CH3:12])(=O)C.O1CCOCC1.[H][H]>O.[Pd]>[CH3:12][C:11](=[CH:10][CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][OH:4])[CH3:15])[CH3:13]
Reactant: CC(=O)OCCC(C)=CCCC(C)(C)Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)=CCCC(C)CCO
Yield: 70 %

Procedure:
1 mole of 7-chloro-3,7-dimethyl-3-octenyl acetate was dissolved into 200 milliliters of dioxane and the solution was subjected to hydrogenation reaction in a reactor containing 20 grams of activated palladium black at about 25° C. under normal pressure until hydrogen was no more absorbed. Then, palladium black was filtered off, from the reaction mixture and dioxane was distilled off from the filtrate under reduced pressure. The residual liquid was added to the solution of 40 grams of sodium hydroxide in 200 milliliters of methanol, and heated under reflux for 72 hours. The resulting reaction mixture was diluted with 1200 milliliters of water, and the oil layer was separated from the aqueous layer. The oil layer thus separated was washed with 200 milliliters of water three times and then dried over 20 grams of Glauber's salt (sodium sulfate). By distillation of the oil layer under reduced pressure a fraction having a boiling point range of 110°-118° C./15mmHg was collected, whereby 0.7 mole of citronellol was obtained.
Reaction SMILES: [O:1]=[C:2]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH:28]1([S:33][CH2:34][CH2:35]Cl)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[O:1]=[C:2]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:35][CH2:34][S:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:7][C@@H:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: ClCCSC1CCCC1
Reactant: COC(=O)C[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 65 °C
Reaction time: 17 h
Yield: 39.4 %

Procedure:
A mixture of 4.9 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate, 2.9 g of 2-chloroethyl cyclopentyl sulfide, 9 g of potassium carbonate, and 2.7 g of potassium iodide in 130 cm3 of acetonitrile was stirred for 17 hours at a temperature in the region of 65° C. After cooling to a temperature in the region of 20° C., the reaction mixture has 150 cm3 of water added and was extracted with 3 times 60 cm3 of ethyl acetate. The organic extracts were combined, washed with 2 times 50 cm3, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. An oil was obtained, which product was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 4 cm; silica volume 300 cm3), elution was carried out with pure ethyl acetate, and approximately 70-cm3 fractions were collected. The fractions comprising the expected product were combined and then concentrated under the above conditions. 2.6 g of methyl (3R,4R)-4-(3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate were obtained in the form of an oil with a yellow color.
Reaction SMILES: [CH3:1][CH:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:15][C@@H:16]2[O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH2:3]O.P(Br)(Br)[Br:35]>N1C=CC=CC=1>[Br:35][CH2:3][CH:2]([CH3:1])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:15][C@@H:16]2[O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
IN 1 ml of pyridine was dissolved 75 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-dien-21 -ol and, then, under ice-cooling, 0.05 ml of phosphorus tribromide was added. The mixture was stirred at the same temperature for 15 minutes. The reaction mixture was then poured into ice water and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 53 mg of 21-bromo-20-methyl-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+].O>CC(=O)CC>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1-2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2

Procedure:
A mixture of 18.8 g (0.05 mole) of 2,7-bis(4-chlorobutyryl)fluorene, prepared in Example 10, 34.0 g (0.4 mole) of piperidine, 16.6 g (0.1 mole) of potassium iodide in 200 ml of butanone is stirred and refluxed for three days. The reaction mixture is poured into 1000 ml of water, and the solid which is precipitated is filtered and recrystallized twice from chloroform-acetone to give 2,7-bis(4-piperidinobutyryl)fluorene, M.P. 157°-159° C.