Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[CH:34]=[CH:35][C:36]([N:39]([CH3:41])[CH3:40])=[N:37][CH:38]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[CH:38]=[N:37][C:36]([N:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1ccc(N(C)C)nc1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(N(C)C)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 24 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and (5-ethynyl-pyridin-2-yl)-dimethyl-amine in the same manner as Example 15. ESI MS m/z 578 [C29H35N7O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4.C(N(CC)CC)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>C1C=CC=CC=1>[CH:29]1([C:33]([N:19]2[CH2:18][CH2:17][C@@:14]34[C:15]5[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(O)CCC(=O)C3
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc2c(c1)[C@]13CCN(C(=O)C4CCC4)[C@H](C2)[C@]1(O)CCC(=O)C3

Procedure:
In an anhydrous system 32 g of 3-methoxy-14-hydroxy-6-ketomorphinan, 16 ml triethylamine and 300 ml of benzene are stirred together and, over a 30 minute period, a solution of 13 g of cyclobutylcarbonylchloride in 100 ml of benzene is added. The internal temperature is kept below 25° by means of an ice bath, after which stirring is continued for four more hours at room temperature. In the isolation, triethylaminehydrochloride is removed by filtration, the solvent evaporated, and the residue solidified by stirring in 200 ml of petroleum ether to give crude N-cyclobutylcarbonyl-3-methoxy-14-hydroxy-6-ketomorphinan.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].Br[CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].O>CN(C)C=O>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Temperature: 20 °C
Yield: 76.7 %

Procedure:
add 561 mg of anhydrous potassium hydroxide to a solution of 1.54 g of 4-amino-3-nitrophenol in 6 cm3 of N,N-dimethylformamide. Add dropwise, to the purple solution obtained, 2.4 g of 2-(bromomethyl)-1,3-dichlorobenzene in solution in 2 cm3 of N,N-dimethylformamide, without exceeding 20° C. After stirring the reaction mixture for about twenty hours at a temperature around 20° C., the reaction mixture is poured into 200 cm3 of water. The mixture obtained is extracted three times with 100 cm3 of ethyl acetate. The combined organic phases are washed five times with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). The residue is taken up successively in a 50/50 mixture of diethyl oxide and diisopropyl oxide, and finally drained, washed three times with 2 cm3 of diisopropyl oxide, then dried under reduced pressure in the presence of potassium hydroxide. We obtain 2.4 g of 4-[(2,6-dichlorobenzyl)oxy]-2-nitroaniline in the form of a white powder, which has the following characteristics:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M49) (350 mg, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (153 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([C:20]([C:35]4[CH:43]=[CH:42][C:38]([C:39]([OH:41])=O)=[CH:37][CH:36]=4)=[C:21](/[CH:23]=[CH:24]/[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[N:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[NH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([C:20]([C:35]4[CH:36]=[CH:37][C:38]([C:39]([NH:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:41])=[CH:42][CH:43]=4)=[C:21](/[CH:23]=[CH:24]/[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[N:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: O=C(O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Compound 40 (0.21 g, 0.36 mmol, Example 5) in DMF (3 mL) was added methyl 3-aminopropanoate (0.12 g, 0.89 mmol), HATU (0.20 g, 0.53 mmol) and DIEA (0.37 mL, 2.1 mmol). The resulting mixture was stirred at rt for 16 h and poured into water (20 mL). The aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over MgSO4 and filtered. Upon removal of the solvent, the resultant residue was purified by flash chromatography on silica gel (40-100% EtOAc/heptane) to give compound 7a as a red solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.12 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.92-8.03 (m, 4H), 7.84 (d, J=8.6 Hz, 2H), 7.78 (d, J=8.1 Hz, 1H), 7.65-7.76 (m, 3H), 7.46-7.54 (m, 1H), 6.97 (t, J=6.0 Hz, 1H), 6.13 (d, J=5.6 Hz, 1H), 4.06-4.13 (m, 4H), 3.96-4.03 (m, 4H), 3.76-3.83 (m, 2H), 3.75 (s, 3H), 2.71 (t, J=5.9 Hz, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[CH3:13][O:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=1[C:23]#[N:24].O>C1COCC1.CN(C)C(=O)C>[CH3:13][O:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20]([NH:22][C:8](=[O:9])[C@:7]([OH:12])([CH3:11])[CH2:6][Br:5])[CH:19]=[CH:18][C:17]=1[C:23]#[N:24]
Reactant: COC(=O)c1cc(N)ccc1C#N
Reactant: C[C@](O)(CBr)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)[C@@](C)(O)CBr)ccc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (3.9 ml, 5.3 mmol) was added dropwise to a solution of (2R)-3-bromo-2-hydroxy-2-methylpropionic acid (8.19 g, 44.8 mmol, prepared as described in WO 2005/000794) in 190 ml of THF and 5.8 ml of N,N-dimethyl-acetamide (DMAC) at 5° C. under nitrogen atmosphere. The solution was stirred for 3 h at room temperature. A solution of 5-amino-2-cyanobenzoic acid methyl ester (7.50 g, 4.3 mmol) in 75 ml of THF was added and the reaction mixture was maintained at 50° C. for 3 h and at room temperature for 16 h. The mixture was poured into water, extracted with ethyl acetate, washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude product was stirred in toluene and filtration afforded the purified compound.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C[CH2:38][OH:39]>[Cu]I>[CH3:38][O:39][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: CCO
Reactant: N#Cc1cccc2c1c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: COc1nn(C2CCCCO2)c2cccc(C#N)c12
Temperature: 90 °C
Yield: 35.7 %

Procedure:
A mixture of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (50 mg, 0.142 mmol), CuI (13.5 g 0.071 mmol), CsCO3 (2.7 mg, 0.0142 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (0.0142 mg, 3.5 mmol) in EtOH (0.5 mL) under nitrogen in a sealed vial was heated to 90° C. in a microwave oven for 100 min. The reaction mixture was quenched with water and extracted with EtOAc. The extract was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc to afford 3-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (13 mg, 35.7%). MS (ESI): m/z=258 [M+1]+.
Reaction SMILES: [CH3:1][C@H:2]1[O:4][C@@H:3]1[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.C([S:14][C@@H:15]1[CH2:20][O:19][C@@H:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[O:17][CH2:16]1)(=O)C>>[N:6]1([CH2:5][C@@:3]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)([OH:4])[C@H:2]([S:14][C@@H:15]2[CH2:16][O:17][C@@H:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=3)[O:19][CH2:20]2)[CH3:1])[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: C[C@H]1O[C@@H]1Cn1cncn1
Reactant: CC(=O)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)OC1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1
Yield: 71 %

Procedure:
Reaction was carried out in the same manner as in Example 1 using (2R*,3R*)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and trans-5-(acetylthio)-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxane to obtain the title compound as an oil in a yield of 71%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH:18](Br)[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH:21]([Br:24])[CH2:22]Br)=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:19]2[C:20]([CH3:26])([CH3:25])[CH:21]([Br:24])[CH2:22][O:27]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C(=O)C(Br)Oc1ccc(Cl)cc1)C(Br)CBr
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(=C(Oc2ccc(Cl)cc2)n2ccnc2)OCC1Br
Temperature: 90 °C
Reaction time: 10 h
Yield: 10.3 %

Procedure:
35 g (0.5 mole) of imidazole and 103.5 g (0.75 mole) of potassium carbonate are dissolved in 700 ml of toluene at 60° C. 132 g (0.269 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-1,4,5-tribromo-2-pentanone in 100 ml of toluene are added dropwise to this solution in the course of 20 minutes. The reaction mixture is subsequently stirred at 90° C. for 10 hours and cooled and water is added. The organic phase is separated off, washed with water dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; ethyl acetate/cyclohexane=3:1). 10.6 g (10% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-(4-bromo-3,3-dimethyltetrahydrofuran-2-ylidene)-methane of refractive index nD20 1.5837 are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([C:25]3[S:26][C:27]([F:30])=[CH:28][N:29]=3)CC3C=CC(OC)=CC=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[F:30][C:27]1[S:26][C:25]([NH:15][S:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:33]=2[O:32][CH3:31])=[N:3][N:4]=[CH:5]3)(=[O:13])=[O:14])=[N:29][CH:28]=1
Reactant: COc1ccc(CN(c2ncc(F)s2)S(=O)(=O)c2ccc3c(Cl)nncc3c2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1nncc2cc(S(=O)(=O)Nc3ncc(F)s3)ccc12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
A vial was charged with 1-chloro-N-(5-fluorothiazol-2-yl)-N-(4-methoxybenzyl)phthalazine-6-sulfonamide (Intermediate CCCC) (55.94 mg, 0.120 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, San Diego, Calif., 31.8 mg, 0.144 mmol), Pd(AmPhos)2Cl2 (4.26 mg, 6.02 μmol), potassium phosphate (77 mg, 0.361 mmol), 1,4-dioxane (451 μl), and water (150 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 30 min, the mixture was diluted with MeOH and concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 0 to 7% MeOH/DCM) to give N-(5-fluorothiazol-2-yl)-1-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine-6-sulfonamide (35.18 mg, 0.073 mmol, 60.4% yield) as a cream-colored solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.88 (s, 1H), 9.96 (s, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.22 (dd, J=1.9, 8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.60-7.52 (m, 2H), 7.41 (s, 1H), 3.77 (s, 3H); m/z (ESI) 485.2 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@H:28]3[CH2:32][C@@H:31]([OH:33])[C@H:30]([OH:34])[C@@H:29]3[OH:35])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:35][C@H:29]1[C@@H:30]([OH:34])[C@H:31]([OH:33])[CH2:32][C@@H:28]1[O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C[C@@H](O)[C@H](O)[C@@H]3O)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1[C@H](O)[C@@H](Oc2nc(N3CCNCC3)nc3ccccc23)C[C@H]1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.5 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,2S,3S,4R)-(2,3,4-trihydroxycyclopentan-1-yl)oxy]quinazoline (270 mg) in methanol (5 ml) is added 10% palladium/carbon (54 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 15 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure to give 4-[(1S,2S,3S,4R)-(2,3,4-trihydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (180 mg) as foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:20][Si](C)(C)C)([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:16])[F:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O[Si](C)(C)C)(C1CCN(Cc2ccccc2)CC1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)(C1CCN(Cc2ccccc2)CC1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a stirred solution of 1-benzyl-4-(1,1,1-trifluoro-2-(trimethylsilyloxy)propan-2-yl)piperidine (3 g, 8.3 mmol) in THF (30 mL), tetrabutylammonium fluoride (3.2 g, 12.4 mmol) was added slowly at RT. The reaction mixture was stirred for 3 h. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate. The organic layer was washed with brine solution and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2-(1-benzylpiperidin-4-yl)-1,1,1-trifluoropropan-2-ol product. [M+1]=288.15
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22](C(O)=O)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.C(O)(=O)CS.C(=O)(O)[O-].[Na+]>O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Sc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)c1cc(Sc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 170 °C
Yield: 37.2 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (89) (1.0 g, 2.13 mmol) and thioglycolic acid (21.3 mL, 2.13 mmol) were heated at 170° C. for 3.5 h. At this time, the reaction was cooled to 25° C. and diluted with water (500 mL). The aqueous layer was brought to pH=4 by the addition of a saturated aqueous sodium bicarbonate solution. The solids that precipitated were collected by filtration, washed consecutively with water, petroleum ether, a pH=5 buffer and water. The solids were air-dried under house vacuum for 15 min and then dried under vacuum to give a light brown solid. This solid was dissolved in a 1N aqueous sodium hydroxide solution (100 mL) and extracted with ethyl acetate (1×120 mL). The aqueous layer was neutralized by the addition of a 1N aqueous hydrochloric acid solution (15 mL). The resulting solids were collected by filtration, washed with water (200 mL) and petroleum ether (100 mL), air-dried under house vacuum and then dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-2H-[1,2,4]triazine-3,5-dione (90) (338 mg, 37%) as tan solid; ES(+)-HRMS m/e calcd for C16H13Cl2N5O3S (M+H)+ 426.0189, found 426.0189. Exact Mass=425.0116; Molecular weight=426.28
Reaction SMILES: Br[CH:2]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][N:8]([CH3:11])[C:9]=1[CH3:10])[CH2:3]Br.[OH-].[K+]>C1(C)C=CC=CC=1>[C:2]([C:5]1[C:6]([C:12]([F:14])([F:15])[F:13])=[N:7][N:8]([CH3:11])[C:9]=1[CH3:10])#[CH:3]
Reactant: Cc1c(C(Br)CBr)c(C(F)(F)F)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1c(C(F)(F)F)nn(C)c1C
Yield: 81 %

Procedure:
7.3 g (20.9 mmol) of 4-(1,2-dibromoethyl)-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole are taken up in 5 ml of toluene and heated to 70° C. for 12 h together with a 60% aqueous KOH solution (10 ml) and 1.2 g of polyethylene glycol 600. After the end of the reaction, the two phases are separated, the aqueous phase is extracted with toluene and the combined organic phases are dried over MgSO4 and concentrated. The product is obtained as a solid in an 81% yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:49])([CH3:48])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:47])([C@@:18]4([CH3:46])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:49])([CH3:48])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:47])([C@@:18]4([CH3:46])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 43.2 %

Procedure:
To a solution of methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.025 g, 0.037 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.5 mL, 0.500 mmol). The mixture was warmed to 60° C. for 15. 5 h then was cooled to rt and purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (11 mg, 0.016 mmol, 42.2% yield) as a white solid. LCMS: m/e 659.5 (M+H)+, 1.77 min (method 2). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.82 (t, J=6.9 Hz, 1H), 6.91 (d, J=6.1 Hz, 1H), 6.86 (d, J=11.9 Hz, 1H), 5.27 (d, J=4.6 Hz, 1H), 4.71 (s, 1H), 4.58 (s, 1H), 3.54-3.43 (m, 3H), 3.39-3.31 (m, 1H), 1.68 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H), 0.90 (s, 3H), 0.90 (s, 3H), 2.75-0.66 (m, 29H).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6](O)[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].CS(Cl)(=O)=O.[OH-].[Na+].CS([O-])(=O)=O.[Na+].C>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:7]1[O:8][C@@H:3]2[C@H:2]3[CH2:1][O:5][C@@H:4]2[C@@H:6]1[O:10]3
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C1O[C@H]2[C@@H]3OC[C@H]2O[C@H]13

Procedure:
To a solution of 2923 g. (20 mol) 1.4;3.6-dianhydro-D-glucitol in 16 liters of anhydrous pyridine, one adds dropwise, with stirring and cooling to -15°, 2 liters (25 mol) methanesulphonic acid chloride, stirs for 15 hrs. at -15° and distils off the pyridine under reduced pressure. The oily residue is mixed with 10 liters of water, briefly heated to boiling and, after cooling, filtered off from 1.4;3.6-dianhydro-D-glucitol 2,5-dimethanesulphonate which has crystallised out and the filter cake is washed 2 times with 2.5 liters amounts of water. The combined filtrates are, after the addition of 1 kg. (25 mol) sodium hydroxide, evaporated under reduced pressure. The residue, consisting of a mixture of 1.4;3.6-dianhydro-D-glucitol 2- and 5-methanesulphonate and sodium methanesulphonate, is, without further purification, subjected to aqueous ammonolysis. For this purpose, one mixes with 4 liters of water and 12 liters of 25% aqueous ammonia and heats the solution thus obtained for 2 days, with stirring, in a closed steel autoclave to 120° (pressure: about 7-8 bar). After cooling and decompressing, one adds 400 g. active charcoal thereto, filters, concentrates the filtrate to about 4 liters and extracts therefrom twice with 1 liter amounts of chloroform the 1.4;2.5;3.6-trianhydro-D-mannitol formed as by-product (in all about 90 g.=0.7 mol) from the 1.4;3.6-dianhydro-D-glucitol 2-methanesulphonate. The aqueous phase is brought to pH=9 by the addition of sodium hydroxide and evaporated to dryness. The semi-solid residue is, for the separating off of inorganic material, boiled with 10 liters of ethanol and, after cooling, filtered. The evaporated filtrate is dissolved, with warming, in 10 liters of n-butanol, dried over anhydrous sodium sulphate, filtered, evaporated and fractionally distilled in vacuo. After a pre-running (0.4 mm.Hg 122°-135°) of 55 g. (0.38 mol) 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol slightly contaminated with trianhydro-D-mannitol, there distil, between 140° and 144° at 0.15 to 0.2 mm.Hg, a total of 681 g. (4.69 mol) pure 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol as a slowly solidifying pale yellowish oil. M.p. (after recrystallisation from chloroform/ethyl acetate/ether) 103°-4°; [α]D25 31.6 (c 2.0; water).