Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1([F:37])[CH2:8][CH:7]([CH2:9][O:10][CH2:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[N:27][CH:26]=4)=[C:21]([O:32][CH3:33])[CH:20]=3)[N:15]=[C:14]([C:34](=[O:36])[CH3:35])[CH:13]=2)[CH2:6]1>C1COCC1>[F:37][C:5]1([F:4])[CH2:8][CH:7]([CH2:9][O:10][CH2:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[N:27][CH:26]=4)=[C:21]([O:32][CH3:33])[CH:20]=3)[N:15]=[C:14]([C:34]([OH:36])([CH3:1])[CH3:35])[CH:13]=2)[CH2:6]1
Reactant: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)=O)n2)ccc1-c1cnnc(C)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)(C)O)n2)ccc1-c1cnnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of methylmagnesium bromide (1.430 mL, 2.00 mmol) in THF (6 mL) a solution of 1-(6-(((3,3-difluorocyclobutyl)methoxy)methyl)-2-(3-methoxy-4-(6-methylpyridazin-4-yl)phenylamino)pyrimidin-4-yl)ethanone (94 mg, 0.20 mmol) in THF (3 mL) was added over 5 min. The mixture was stirred on ice-bath for 30 minutes before it was quenched with ammonium chloride (aq, sat). The solvent volume was reduced by evaporation. The mixture was extracted with dichloromethane and the organic phase was passed through a phase separator. The residue was purified by preparative HPLC to give the title compound as a dry film 38 mg (39%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](Cl)(=[O:10])[C:7]([Cl:9])=[O:8]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:10])[C:7]([Cl:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
t-Butanol (765 μL, 8.0 mmol) was added dropwise to a solution of oxalyl dichloride (1.0 mL, 12.0 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at room temperature for 1 hour then concentrated in vacuo to yield chloro-oxo-acetic acid t-butyl ester as a clear colorless liquid (1.1 g). A 1 M solution in DCM was prepared by dissolving the liquid (1.1 g, 6.7 mmol) in DCM (6.7 mL).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.CN(C=O)C.[NH:35]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]1>CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([N:35]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]2)=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Reactant: OC1CCNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCC(O)C2)cc1F
Temperature: 110 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (40 mg, 0.088 mmol) in pyrrolidin-3-ol (0.4 ml) was added DMF (0.5 ml). The mixture was stirred for 12 hours at 110° C. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (40 mg, 91%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1N
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-ylamine (130 mg, 0.46 mmol) in THF (6 ml) was added a solution of K2CO3 (126 mg, 0.91 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.05 ml, 0.48 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (1.9 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (2 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (30 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 77 mg (56%) of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil. ES-MS m/e: 299.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7](OS(C)(=O)=O)[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[C-:22]#[N:23].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7]([C:22]#[N:23])[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: [C-]#N
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A mixture of (4R)-1-(tert-butyloxycarbonyl)-4-(methane-sulfonyloxy)-L-proline methyl ester (2.31 g, 7.14 mmol) and sodium cyanide (3.5 g, 71.4 mmol) in dry dimethylsulfoxide (46 mL) was stirred for 24 hours at 55° C. under a nitrogen atmosphere. The cooled reaction mixture was diluted with ethyl acetate, washed with water (2×), saturated brine solution, dried (MgSO4), and evaporated. The crude product mixture was subjected to flash silica gel chromatography eluting with 15% acetone/hexane. Fractions containing the desired nitrile were combined and evaporated to afford a colorless oil; yield 205 mg (11%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:23])=[CH:6][C:7]=1[C:8]([CH3:22])([CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:9].[Br-:24].[Li+]>CS(C)=O>[Br:24][CH2:10][C:8]([C:7]1[CH:6]=[C:5]([CH3:23])[N:4]=[N:3][C:2]=1[Cl:1])([CH3:22])[CH3:9]
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)c2cc(C)nnc2Cl)cc1
Agent: [Li+]
Solvent: CS(C)=O
Product: Cc1cc(C(C)(C)CBr)c(Cl)nn1

Procedure:
A 0.6 g. portion of 3-chloro-4-(1-methyl-1-p-toluenesulfonyloxymethylethyl)-6-methylpyridazine was dissolved in 10 ml. of dimethylsulfoxide and was reacted with 0.3 g. of lithium bromide at 110°, as described in examples above, to obtain 200 mg. of the desired product, a light yellow oil, the identity of which was confirmed by mass spectroscopy. A molecular ion of weight 262 was observed, as was the ion of weight 169 which resulted from loss of the bromomethyl group from the compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:20][O:21][C:22](=[O:45])[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:20][O:21][C:22](=[O:45])[CH2:23][CH:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[CH:7]=[N:6][C:5]([NH:8][C:9]4[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][CH:3]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:29]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1nc(C(F)(F)F)ccc1Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4C)nc3)cc2)CC1
Temperature: 80 °C

Procedure:
(5-Bromo-pyridin-2-yl)-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-amine (290 mg, 0.87 mmol) and {4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (312 mg, 0.87 mmol) were dissolved in anhydrous DME (3 mL) in a pressure vessel. PdCl2dppf (21 mg, 0.026 mmol) was added, followed by aqueous sodium carbonate (2M, 0.870 mL, 1.74 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and heated at 80° C. for 18 hours. The mixture was partitioned between EtOAc and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via column chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (7-50%) to obtain the target compound as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.21 (m, 2H) 1.50 (td, J=12.44, 10.23 Hz, 2H) 1.81 (m, 4H) 2.25 (d, J=6.57 Hz, 2H) 2.59 (s, 3H) 3.60 (s, 3H) 7.22 (d, J=8.59 Hz, 1H) 7.31 (d, J=8.34 Hz, 2H) 7.57 (d, J=8.34 Hz, 2H) 7.66 (d, J=8.59 Hz, 1H) 7.97 (dd, J=8.59, 2.53 Hz, 1H) 8.48 (d, J=2.53 Hz, 1H) 8.64 (s, 1H) 8.66 (d, J=8.34 Hz, 1H); MS-(M+H)+484.3.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C@H:22]([NH2:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36](=[O:37])[CH2:35][CH:34]([CH:38]=O)[CH2:33]2)=[CH:28][CH:27]=1>CC(O)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C@H:22]([NH:24][CH2:38][CH:34]2[CH2:33][N:32]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[C:36](=[O:37])[CH2:35]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1
Reactant: O=CC1CC(=O)N(c2ccc(F)cc2)C1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@@H](NCC1CC(=O)N(c2ccc(F)cc2)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with sodium triacetoxyborohydride (1.0 g, 4.8 mmol), (R)-1-(3-chlorophenyl)ethanamine 55 (0.413 g, 2.7 mmol), 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carbaldehyde 54 (0.500 g, 2.4 mmol), 10 mL of DCE, and 5 drops of AcOH. This mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3. The mixture was extracted with DCM, dried, concentrated, and purified by column chromatography on silica gel (3% to 7% MeOH in DCM) to give 4-({[(1R)-1-(3-chlorophenyl)ethyl]amino}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one 56 as a 1:1 mixture of diastereomers. Mass spectrum: calculated for C19H20ClFN2O 346.1; found 347.2 (M++1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[CH:18]([Mg]Br)([CH3:20])[CH3:19]>O1CCCC1.[Cu]I>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH:9]([C:12]#[N:13])[C:10]#[N:11])[CH:18]([CH3:20])[CH3:19])=[CH:14][CH:15]=1
Reactant: N#CC(C#N)=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(OC(F)(F)F)cc1)C(C#N)C#N
Yield: 55 %

Procedure:
Using 1.19 g of (4-(trifluoromethoxy)benzylidene)malononitrile, 20 ml of tetrahydrofuran, a catalytic amount of copper (I) iodide, and a solution of isopropyl magnesium bromide in tetrahydrofuran (prepared from 0.39 g of magnesium, 10 ml of tetrahydrofuran, and 2.36 g of isopropyl bromide), and according to the process described in Reference Production Example 2, there was obtained 0.77 g of (1-(4-(trifluoromethoxy)phenyl)-2-methylpropyl)malononitrile (the intermediate (8)).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(C)n1
Product: Cc1cccc(C(=O)C=CN(C)C)n1

Procedure:
A mixture of 25.0 g of 2-acetyl-6-methylpyridine and 35 ml. of N,N-dimethylformamide dimethylacetal is refluxed for 16 hours. The mixture is cooled and filtered to give 3-dimethylamino-1-(6-methyl-2-pyridyl)-2-propen-1-one as crystals, m.p. 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([CH2:29][CH2:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)(O)CCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 8 h

Procedure:
To a mixture of the title compound of Example 5 (0.457 g), copper iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 mL diethylamine is added 2-methyl-3-butyne-2-ol (0.097 mL). The reaction is allowed to stir overnight. The solvents are evaporated and the residue is chromatographed on silica, eluting with 3% MeOH/CH2Cl2 to yield 0.248 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[O:46]1[CH:50]=[CH:49][C:48]([CH2:51]O)=[CH:47]1.C(P(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:51][C:48]1[CH:49]=[CH:50][O:46][CH:47]=1)[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: OCc1ccoc1
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(Cc2ccoc2)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide (0.015 g) in THF (0.5 ml) was treated with diisopropyl azodicarboxylate (0.01 ml), 3-furanmethanol (0.004 ml) and tri-n-butylphosphine (0.008 ml) and shaken at room temperature for 60 h. The mixture was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.015 g) as a colourless gum.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[C:13]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][O:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([Br:3])=[CH:5][C:6]=1[F:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(F)cc(Br)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)cc(Br)cc1F
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Methyl iodide (17.11 g, 0.12 mol) was added at 0° C. to a well stirred suspension of 4-bromo-2,6-difluorophenol (21 g, 0.1 mol; see step (i) above) and K2CO3 (27.78 g, 0.2 mol) in dry acetone (150 mL). Stirring was continued at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered, the solvent was evaporated and the residue was purified by column chromatography over silica gel, using petroleum ether as eluent, to give 11.5 g of the sub-title compound as a colourless liquid.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].F[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20].CCOC(C)=O>O>[CH3:18][NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:6][CH:3]([CH3:5])[CH3:4])=[C:9]([N+:19]([O-:21])=[O:20])[CH:10]=1)(=[O:16])=[O:15]
Reactant: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(OC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
NaH (0.440 g, 11 mmol) was added to 20 mL of isopropanol and the resulting mixture stirred at room temperature. After 30 minutes, 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (2.34 g, 10 mmol) was added. The reaction mixture was then stirred at room temperature overnight. The mixture was poured into EtOAc and water. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product. Purification via column chromatography (1:1 petroleum ether/ethyl acetate) afforded N-methyl-4-[(1-methylethyl)oxy]-3-nitrobenzenesulfonamide (1.6 g, 58% yield) as a yellow solid. MS (m/z) 274.7 (M+H+)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]([CH3:17])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2].[NH2:21][OH:22]>C(O)C>[NH2:2][C:1](=[N:21][OH:22])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]([CH3:17])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11]
Reactant: CN(CCC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Reactant: NO
Solvent: CCO
Product: CN(CCC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl 3-[(3-cyanobenzyl)(methyl)amino]propanoate (4.5 g, 0.0164 mol) in ethanol (60 mL) under N2, was added hydroxylamine (2.5 mL, 0.082 mol) in one portion. After being stirred at RT for 12 h, the reaction mixture was concentrated under reduced pressure to afford the title compound as a white gummy solid (4.5 g, 84%). 1H NMR (DMSO-d6, 400 MHz) δ 9.56 (s, 1H), 7.51-7.53 (m, 2H), 7.27-7.31 (m, 2H), 5.74 (s, 2H), 3.44 (s, 2H), 2.55-2.59 (m, 2H), 2.34-2.38 (m, 2H), 2.09 (s, 3H), 1.37 (s, 9H). LC/MS (Method A): 308.2 (M+H)+. HPLC (Method B) Rt 5.18 min (Purity: 96.5%).
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]3([C:16]([CH2:18][OH:19])=[O:17])[O:11][C:12]([CH3:15])(C)[O:13][C@@H:9]3[CH2:8][C@H:7]1[C@@H:6]1[CH2:20][CH2:21][C:22]3[C@@:28]([CH3:29])([C@H:5]1[C@@H:4]([OH:30])[CH2:3]2)[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3.[CH:31](=O)[CH2:32]CC.F>O>[CH3:31][CH2:32][CH2:15][CH:12]1[O:11][C@:10]2([C:16]([CH2:18][OH:19])=[O:17])[C@@H:9]([CH2:8][C@@H:7]3[C@:2]2([CH3:1])[CH2:3][C@H:4]([OH:30])[C@H:5]2[C@H:6]3[CH2:20][CH2:21][C:22]3[C@:28]2([CH3:29])[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3)[O:13]1
Reactant: CC1(C)O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Reactant: CCCC=O
Agent: F
Solvent: O
Product: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 Grams of desonide (16α-hydroxyprednisolone-16,17-acetonide) and immediately thereafter 12,5 ml of butyraldehyde were added to 500 ml of a 70% hydrofluoric acid solution, at -5° C. The mixture was stirred at 0° C. for one hour and then poured into 5 liters of demineralized water at 0° C. The precipitate was filtered, washed to neutrality with water and dried under vacuum to give 51 g of pure budesonide with an A/B epimer ratio of 9/91.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20](/N=C/N(C)C)=[O:21])=NC=1.NN>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:20][O:21]3)[N:9]=2)=[N:6][CH:7]=1
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cn1
Reactant: Brc1ccc(-c2nc[nH]n2)nc1
Agent: NN
Product: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Yield: 83 %

Procedure:
5-Bromo-2-(1H-1,2,4-triazol-3-yl)pyridine. A solution of (E)-5-bromo-N-((dimethylamino)methylene)picolinamide (0.604 mg, 2.36 mmol) and hydrazine (2.12 g, 66.1 mmol) was stirred at 25° C. for 3 h. The reaction was concentrated and diluted with water. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (0.442 g, 83% yield). MS (ESI) m/z 226.1 [M+1]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[C:7]([C:12]2[N:25]([CH3:26])[C:15]3=[N:16][CH:17]=[C:18]([S:20][C:21]([F:24])([F:23])[F:22])[CH:19]=[C:14]3[N:13]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:6]1[C:7]([C:12]2[N:25]([CH3:26])[C:15]3=[N:16][CH:17]=[C:18]([S:20]([C:21]([F:24])([F:22])[F:23])=[O:35])[CH:19]=[C:14]3[N:13]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccnc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1-c1nc2cc(S(=O)C(F)(F)F)cnc2n1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a mixture of 2-(3-ethylsulfonyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (500 mg) and chloroform (10 ml) was added m-chloroperbenzoic acid (purity: not less than 65%) (429 mg) while ice-cooling, and the mixture was stirred at room temperature for 1 hour and at 50° C. for 2 hours. To the reaction mixture were poured aqueous sodium thiosulfate solution and aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfonyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfinyl-3H-imidazo[4,5-b]pyridine (353 mg), which is hereinafter referred to as “the present compound 20”.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.B.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1.CO>C1COCC1>[C:18]1([CH:22]([NH:3][CH2:2][CH2:7][CH:6]2[CH2:7][CH2:2][N:3]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=3)[CH2:4][CH2:5]2)[C:11]2[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=[CH:20][CH:19]=1
Reactant: C1CCOC1
Reactant: CC1CCCCN1Cc1ccc(F)c(F)c1
Agent: B
Solvent: CO
Product: Fc1ccc(CN2CCC(CCNC(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To the solution of 4-[2-diphenylmethyl)aminocarbonyl]methyl-1-[(3,4-difluorophenyl)methyl]piperidine (0.12 g, 0.28 mmol) in dry THF 20 ml was added 1M BH3/THF (1.0 ml). The reaction solution was refluxed for 6 hours. After the solution was cooled to room temperature, MeOH (5 ml) was added slowly. The solvent was removed under reduced pressure. 10% HCl/MeOH (10 ml) was added into the residue and the solution was refluxed for 1 hour. Solid NaHCO3 was added after MeOH was evaporated. The mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated to give the crude product, which was purified by chromatography (Hexane/EtOAc/Et3N=1/2/1%) to a white solid, 0.11 g (90% yield) (“Procedure E”). 1H NMR (CD3Cl) δ 7.39-6.99 (13H, m, Ar—H), 4.79 (1H, s, Ph2CH), 3.39 (2H, s, F2PhCH2), 2.80-2.76 (2H, d, J=11.1 Hz, N(CH)2), 2.60-2.55 (2H, t, J=7.0 Hz, NCH2), 1.93-1.86 (2H, t, J=11.1 Hz, N(CH)2), 1.62-1.58 (2H, d, J=12 Hz), 1.49-1.42 (2H, q, J=6.3 Hz, NCH2CH2), 1.35-1.31 (1H, m, NCH2CH2CH(CH2)2), 1.26-1.19 (2H, t, J=12.0 Hz). The free base was converted into its HCl salt, m.p.=280-281° C. Anal: (C17H30N2F2·2HCl·0.25H2O) Calculated: C, 65.12; H, 6.85; N, 5.62; Found: C, 65.13; H, 6.80, N, 5.28.