Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CC(C)C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CC(C)C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isobutylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (900 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (358 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isobutylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (619 mg) (Compound 382) as yellow amorphous.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH:10]=[N:9]1)(=O)=O.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.ClCCl>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([B:13]([OH:14])[OH:17])[CH:10]=[N:9]2)[CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2cnn(CCOS(C)(=O)=O)c2)OC1(C)C
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(CCn2cc(B(O)O)cn2)CC1
Temperature: 50 °C
Yield: 63.2 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.080 g, 0.253 mmol) in 0.5 mL N,N-dimethylformamide was added 1-methylpiperazine (0.281 mL, 2.53 mmol) and the reaction was sealed under nitrogen and heated to 50° C. for 2.5 hours. The reaction mixture was diluted with dichloromethane (3 mL) and then loaded directly onto a silica gel column pre-wetted and eluted with 15% methanol in dichloromethane containing 1% ammonium hydroxide to afford 1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-ylboronic acid (0.038 g, 0.160 mmol, 63% yield) as a result of hydrolysis on silica in the presence of methanol and ammonium hydroxide. MS (apci) m/z=239.1 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>CO.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2CNC(=O)C2)cc1O
Yield: 99.8 %

Procedure:
A mixture of 4-(3-Benzyloxy-4-methoxyphenyl)-2-pyrrolidone (3.5 g, 11.6 mmol) and 350 mg of 10% Pd/C in 50 mL of MeOH and 10 mL of CH2Cl2 was shaken on a Paar apparatus under a 20 psi atmosphere of hydrogen for 8 hours. The mixture was filtered through celite and concentrated to afford 2.4 g (99%) of 4-(3-Hydroxy-4-methoxyphenyl)-2-pyrrolidone that was used without further purification for the syntheses described in Examples 1-3. 1H NMR (300 MHz, CDCl3) δ 6.82 (s, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.50 (s, 1H), 3.87 (s, 3H), 3.77 (t, J=8.4 Hz, 1H), 3.62 (t, J=8.0 Hz, 1H), 3.40 (t, J=8.4 Hz, 1H), 2.71 (dd, J=16.8, 8.8 Hz, 1H), 2.49 (dd, J=16.8, 9.0 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH3:20]>C(O)C.O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12]([N:19]([CH3:20])[CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=S(=O)(c1ccccc1)c1cc(Br)nc(Br)c1
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)c1cc(S(=O)(=O)c2ccccc2)cc(Br)n1
Yield: 88 %

Procedure:
0.113 g (0.0003 mol) of 4-benzenesulphonyl-2,6-dibromopyridine and 0.54 ml of 5.6 M dimethylamine in ethanol were stirred at room temperature in a mixture of 3 ml of ethanol and 3 ml of dioxan for 5 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:10. There was obtained 0.09 g (88%) of (4-benzenesulphonyl-6-bromopyridin-2-yl) -dimethylamine as white crystals; m.p. 128-130° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]3([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]5([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]5[C:4]=4[N:3]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(-c3ccc(NC(=O)NC4CC4)cc3)ncc21
Yield: 44.4 %

Procedure:
A mixture of 2-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (260 mg, 0.782 mmol), 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (402 mg, 1.33 mmol), saturated aqueous NaHCO3 (2 ml) and PdCl2(dppf) (51.1 mg, 0.063 mmol) in 1,4-dioxane (5 ml) was irradiated in the microwave at 110° C. for 30 minutes The reaction mixture was diluted with THF and passed through 0.45 μM PTFE syringe filter (washed with small amount of THF). The filtrate was purified by preparative HPLC (eluting with a gradient of 20-45% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column). The fractions containing the desired product were combined and were evaporated under reduced pressure. Then NaHCO3 aqueous solution was added (in order to adjust the pH to basic) and extracted with EtOAc (THF was added to dissolve the precipitate). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (164 mg, 0.347 mmol, 44% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35-0.45 (m, 2 H) 0.58-0.71 (m, 2 H) 1.36 (s, 3 H) 1.70 (t, J=19.20 Hz, 3 H) 2.50-2.61 (m, 1 H) 3.19-3.31 (m, 1 H) 3.53-3.73 (m, 2 H) 3.94-4.11 (m, 2 H) 4.12-4.25 (m, 1 H) 4.34-4.52 (m, 1 H) 4.52-4.70 (m, 1 H) 6.46 (d, J=2.53 Hz, 1 H) 7.45-7.55 (m, 2 H) 8.14-8.23 (m, 2 H) 8.39 (s, 1 H) 8.54 (s, 1 H). MS [M+H] found 473.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.C1C(=O)N([Cl:22])C(=O)C1.C(=O)(O)[O-].[Na+]>Cl>[Cl:22][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[C:14]2=1
Reactant: Cc1cncc2[nH]c3ccccc3c12
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cncc2[nH]c3ccc(Cl)cc3c12
Temperature: 25 °C
Yield: 93.7 %

Procedure:
4-methyl-9H-β-carboline (97 mg, 0.532 mmol) was dissolved in HCl (1N, 4 ml) and stirred at RT. NCS (85 mg, 0.637 mmol) was added thereto and the reaction mixture was stirred for 5 hr. Saturated sodium bicarbonate solution (20 ml) was added thereto and the reaction mixture was extracted twice with EtOAc (100 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give 6-chloro-4-methyl-9H-β-carboline (108 mg) as an oil. 1H-NMR (300 MHz, DMSO-d6): δ 8.67 (s, 1); 8.19 (s, 1); 8.11 (s, 1); 7.57-7.54 (m, 2); 2.82 (s, 3). NH4OAc standard conditions. DAD Rf=2.48 min. M+H=217.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=O)[O:9][CH:10](O)[C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.S(O)(O)(=O)=O.[NH2:19][NH2:20].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[NH:19][N:20]=[CH:10][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: NN
Reactant: O=C1OC(O)c2cc(Cl)nc(Cl)c21
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc2cc(Cl)nc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4,6-dichloro-1-hydroxy-1H-furo[3,4-c]pyridin-3-one (9.37 g) stirring in water (100 ml) was added hydrazine sulfate (10.58 ml) and sodium acetate (13.56 g). The reaction mixture was heated at reflux and stirred for 2 h. The reaction mixture was cooled to RT, diluted with water (150 ml) and extracted with EtOAc (2×75 ml). The combined organic layers were washed with saturated Na2CO3 solution and dried over Na2SO4. Evaporation to dryness gave the desired product as brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@H:20]1[O:41][C@@H:21]1[C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:20]([OH:41])[CH2:21][C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1O[C@@H]1[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58.1 %

Procedure:
A mixture of 39.2 g (71.2 mmol) of (2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-epoxy-1,6-diphenylhexane in 600 ml of THF was treated under N2 atmosphere with 13 g (0.36 mol) of sodium borohydride. The resulting mixture was treated dropwise with 27.7 ml (0.36 mol) of trifluoroacetic acid. After being stirred for 3.5 h at ambient temperature, the resulting mixture was quenched with 1N aqueous HCl, diluted with water, and stirred for 16 h. The resulting mixture was filtered. washed with water, and dried to provide 22.85 g (58%) of the desired compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH2:24][C:25]#[N:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl.Cl.C(N=C=NCCCN(C)C)C.[NH4+].[OH:50]N1C2C=CC=CC=2N=N1>C(O)C.O.CN(C)C=O>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH2:24][C:25]([NH2:26])=[O:50])=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(CC#N)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(CC(N)=O)cc12

Procedure:
To a solution of tert-butyl[4-butoxy-6-(cyanomethyl)-2-neopentyl-1oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.45 g, 1 mmol) in ethanol (20 ml) was added a solution of potassium hydroxide (0.40 g, 10 mmol) in water (5 ml). The mixture was refluxed for 10 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude amorphous solid. A solution of the amorphous solid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g, 1 mmol) and 1-hydroxybenzotriazole ammonium salt (0.15 g, 1 mol) in N,N-dimethylformamide (10 ml) was stirred for 2 h at room temperature. The resulting reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give tert-butyl[6-(2-amino-2-oxoethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate. (0.13 g, 54.2%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:4][CH:3]=1.CCO[CH:21](OCC)[CH2:22][CH:23](OCC)OCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]3[N:15]=[CH:21][CH:22]=[CH:23][N:12]3[N:11]=2)=[CH:16][CH:17]=1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: Nc1nc(SCCOc2ccc(Cl)cc2)n[nH]1
Product: Clc1ccc(OCCSc2nc3ncccn3n2)cc1
Yield: 42 %

Procedure:
The title compound was prepared according to the experimentals described for Example 23 above from 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine and malonaldehyde bis(diethyl acetal) in 42% yield; EM (calc.): 306.0; MS (ESI) m/e: 307.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 9.33 (dd, 1H), 8.81 (dd, 1H), 7.31 (m, 3H), 7.02 (dt, 2H), 4.33 (t, 2H), 3.62 (t, 2H).
Reaction SMILES: [N:1]1([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=2[F:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]([C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[C:24]([CH3:31])[N:25]=[CH:26]2)=[C:19]=[O:20].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[N:1]1([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:19]([NH:18][C:21]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:22]=3[CH:23]=[C:24]([CH3:31])[N:25]=[CH:26]4)=[O:20])=[CH:11][C:10]=2[F:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(N2CCCCCCC2)c(F)c1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCCCC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-azocanyl)-3-fluorobenzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.37 (s, 1H), 8.56 (m, 2H), 8.01 (d, 1H, J=8.4 Hz), 7.81 (t, 1H, J=8.4 Hz), 7.45 (t, 1H), 7.02 (m, 2H), 6.90 (m, 1H), 4.25 (d, 2H, J=6 Hz), 3.35 (m, 4H), 2.77 (s, 3H), 1.67 (m, 4H), 1.54 (m, 6H); MS (ESI) 421 (M+H)+; Anal. Calcd for C25H29FN4O.HCl: C, 65.71; H, 6.62; N, 12.26. Found: C, 65.44; H, 6.49; N, 12.15.
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:29])[CH:5]=[C:6]3[C@:26]([CH3:27])([C@@H:2]12)[C@@H:25]1[C@H:9]([C@H:10]2[C@:22]([CH3:28])([CH2:23][CH2:24]1)[C@@H:13]([C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.[Li].N.[Cl-].[NH4+]>CCOCC>[OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:29])[CH2:3]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
A solution of 3.0 g (1 equivalent) of 1α,2α-epoxycholesta-4,6-dien-3-one in 200 ml of absolute ether is added dropwise within 45 minutes with stirring in an argon atmosphere at -31° C. to -33° C. to a solution of 210 mg (4 equivalents) of lithium in 300 ml of liquid ammonia, the liquid ammonia having been dried over sodium and distilled. As soon as the resulting mixture becomes light blue in colour the dropwise addition is quickly interrupted and 52.5 mg (1 equivalent) of lithium are added. After completion of the dropwise addition, the mixture containing cholesta-3,5-diene-1α,3β-diol dilithium salt, is stirred for 15 minutes, the blue colour is removed from the solution by the addition of 0.2 ml of isoprene and, with stirring, a total of 2.025 g 5 equivalents) of ammonium chloride are added in portions within 4 minutes. The resulting stirred yellowish mixture is treated under argon at -31° C. to -33° C. in the same manner with 2.312 g (5.7 equivalents) of ammonium chloride, and then with 298 mg (5.7 equivalents) of lithium; and as soon as these additions have reacted, the same procedure, i.e. the addition of 5.7 equivalents of ammonium chloride followed by 5.7 equivalents of lithium, is repeated a further four times. The mixture is thereafter treated with 10 g of ammonium chloride, and ammonia is evaporated until the temperature of the mixture has reached 0° C. The suspension is treated with 50 ml of saturated ammonium chloride solution and, after dilution with 200 ml of water, is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated at 40° C./11 Torr. The crude product, 3.3 g, is chromatographed on a column of 60 g of silica gel prepared in hexane/ether (9:1). Elution with 400 ml of hexane/ether (4:1) and 1.3 liters of hexane/ether (1:1) yields 0.55 g of apolar fractions and with 2.5 liters of ether yields 2.472 g (81%) of crystalline 1α-hydroxycholesterol. After recrystallisation from acetone, this substance melts at 157°-159° C.; [α]D25 =-39.6° (c=0.5 in chloroform).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.[C-:22]#[N:23].[Na+]>CS(C)=O>[C:10]1([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][CH2:6][C:22]#[N:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)OCCCC(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCC(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of 4,4-diphenylbutyl methanesulfonate (7.5 g) and sodium cyanide (2.5 g) in dimethyl sulfoxide (70 mL) was stirred at 60° C. for 15 hours. After the reaction mixture was allowed to cool, it was extracted with diethyl ether. The extract was dried over MgSO4 and concentrated, whereby 5.8 g of the title compound was obtained quantitatively.
Reaction SMILES: [Cl:1]C1C=CC(C(F)(F)F)=CN=1.[ClH:12].[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28]([Cl:30])=[O:29])=[CH:24][CH:23]=2)=[N:19][CH:20]=1>BrC(CC)C(O)=O>[ClH:1].[Cl:12][C:17]1[C:18]([O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28]([Cl:30])=[O:29])=[CH:24][CH:23]=2)=[N:19][CH:20]=[C:15]([C:14]([F:34])([F:35])[F:13])[CH:16]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Agent: CCC(Br)C(=O)O
Agent: Cl
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl

Procedure:
By using 2-chloro-5-trifluoromethylpyridine instead of 2,3-dichloro-5-trifluoromethylpyridine in the above (b), 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride hydrochloride was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1.BrCC1CCCCO1.[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]2[C:29]3([CH2:39][O:40][C:23]=2[CH:22]=1)[C:37]1[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)[NH:31][C:30]3=[O:38]>>[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]2[C:29]3([CH2:39][O:40][C:23]=2[CH:22]=1)[C:37]1[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)[N:31]([CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1)[C:30]3=[O:38]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: COc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1F)OCC21C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-bromomethyl-2-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 6-fluoro-5-methoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: mp 132-134° C.; 1H NMR (300 MHz, CDCl3) δ7.58 (d, J=9.4 Hz, 1H), 7.27 (dd, J=7.7, 7.7 Hz, 1H), 7.06-7.01 (m, 2H), 6.84 (d, J=7.9 Hz, 1H), 6.71-6.67 (m, 2H), 6.62 (d, J=12.1 Hz, 1H), 6.34 (d, J=3.4 Hz, 1H), 6.10 (d, J=3.4 Hz, 1H), 4.90 (d, J=16.3 Hz, 1H), 4.57 (d, J=12.8 Hz, 1H), 4.45 (d, J=12.7 Hz, 1H), 4.41 (d, J=16.2 Hz, 1H), 3.91 (s, 3H); MS (ES+) m/z 433.9 (M+1).
Reaction SMILES: CC(C)(OC([N:7]([N:15]=[CH:16][NH:17][CH2:18][CH2:19][CH2:20][CH:21]([P:30]([O:35]CC)(=[O:34])[O:31]CC)[P:22]([O:27]CC)(=[O:26])[O:23]CC)C(OC(C)(C)C)=O)=O)C>Cl>[NH2:7][N:15]=[CH:16][NH:17][CH2:18][CH2:19][CH2:20][CH:21]([P:30]([OH:35])(=[O:31])[OH:34])[P:22]([OH:26])(=[O:23])[OH:27]
Reactant: CCOP(=O)(OCC)C(CCCNC=NN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)P(=O)(OCC)OCC
Agent: Cl
Product: NN=CNCCCC(P(=O)(O)O)P(=O)(O)O

Procedure:
A solution of 0.92 g (2.56 mmol) of tetraethyl 4-((bis(1,1-dimethylethoxycarbonyl)aminoiminomethyl)amino)butane-1,1-bisphosphonate in 15 ml of concentrated hydrochloric acid is heated at boiling point for 12 hours. After concentration, the residue is treated with ethanol. The precipitate is filtered off with suction under reduced pressure and dried under reduced pressure. It is recrystallized from ethanol/water.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][OH:21])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.I[CH:24]([CH3:26])[CH3:25].Cl>C1COCC1.O>[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][O:21][CH:24]([CH3:26])[CH3:25])[N:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)I
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOC(C)C)cs1
Reaction time: 0.25 h

Procedure:
Sodium hydride (95% dry, 129 mg, 5.39 mmol) was added to a stirred solution of EXAMPLE 181A (359 mg, 1.08 mmol) in THF (10 mL) at room temperature. After stirring for 15 min, the mixture was treated with 2-iodopropane (917 mg, 5.39 mmol). After two days at 50° C., additional sodium hydride (26 mg, 1.08 mmol) and 2-iodopropane (366 mg, 2.16 mmol) were added. After stirring for 1 h the reaction mixture was acidified with 2M HCl and water was added. The product was extracted with DCM and dried (sodium sulfate). Evaporation of the solvent gave a residue which was purified by flash chromatography on silica gel eluting with 4% acetone in DCM giving (15 mg, 4%) of an oil which solidified on standing: MS (Ionspray, [M+H]+) m/z 374.