Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]3[C:30]([N:31](S(C)(=O)=O)[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][N:28]=[C:27]([N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[N:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl>CO.C1COCC1>[N:1]1([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]3[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][N:28]=[C:27]([N:40]([CH2:41][CH3:42])[CH2:43][CH3:44])[N:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)c1ncc(N(S(C)(=O)=O)S(C)(=O)=O)c(N[C@@H](Cc2ccc(OC(=O)N3CCCC3)cc2)C(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)c1ncc(NS(C)(=O)=O)c(N[C@@H](Cc2ccc(OC(=O)N3CCCC3)cc2)C(=O)OC(C)(C)C)n1
Temperature: 40 °C
Yield: 85.7 %

Procedure:
Compound 10 (2.2 g, 3.4 mmol) was dissolved in methanol (5 mL) and THF (5 mL). 1.0 M K2CO3 (10 mL) was added and the reaction mixture was heated at 40° C. for 96 hours. The reaction mixture was acidified to pH 3 with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 1.68 g (86%) product as a beige foam, compound 11. The crude material was used without purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][C:18](/[CH:20]=[CH:21]/[NH2:22])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].CO.O>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][C:18]([CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: N/C=C/c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a suspension of lithium aluminium hydride (0.939 g, 24.8 mmol) in THF (20 ml) under nitrogen atmosphere at 0° C. was added slowly a solution of (E)-2-(5-(3,4-dichlorophenyl)furan-2-yl)ethenamine in THF (20 ml). Reaction mixture was stirred at RT for 1 h. Some methanol was added slowly to the mixture followed by addition of water. The mixture was evaporated, and the solid residue was extracted with EtOAc (3×). Combined EtOAc fractions were washed with 2M NaOH and brine. Organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, silica column, eluent: 10-20% MeOH/DCM) to give 227 mg (11%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.74 (t, 2H), 2.85 (t, 2H), 6.29 (d, 1H), 7.03 (d, 1H), 7.62 (dd, 1H), 7.63 (d, 1H), 7.88 (d, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[O:7][N:6]=1)=[N+]=[N-].C(N(CC)CC)C.C(S)CCS.[H-].[Na+]>CC(O)C>[F:13][C:10]([F:11])([F:12])[C:8]1[O:7][N:6]=[C:5]([CH2:4][NH2:1])[CH:9]=1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)on1
Agent: SCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: NCc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
To a solution of 6.26 g 3-(azidomethyl)-5-(trifluoromethyl)isoxazole in 100 mL 2-propanol were added 9.08 mL triethyl amine and 330 uL 1,3-propanedithiol. 2.45 g sodiumhydride were added portion wise and stirred at RT for 16 h. The reaction mixture was concentrated in vacuo. The residue was poured carefully into 180 mL 10% acetic acid and washed with diethyl ether/heptane mixture 1.1 (3×50 mL) The aqueous layer was basified with conc. NaOH to pH=12 (50 mL), saturated with NaCl and extracted with CH2Cl2 (3×250 mL). The combined organic layer was dried over Na2SO4, filtered off and concentrated in vacuo to yield 3.4 g of the title compound as yellow oil; LC-MS (UV peak area/ESI) 97.6%, 167.043 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19]Cl)([O:17]Cl)=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[O:4].[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>CCOCC>[F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19][NH:27][CH2:23][CH2:24][CH2:25][CH3:26])([O:17][NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[O:4]
Reactant: COCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: CCCCN
Solvent: CCOCC
Product: CCCCNOP(=O)(CN(CC(=O)OCCOC)C(=O)C(F)(F)F)ONCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 2-methoxyethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (7.45 g, 0.0207 mole) in 125 ml. of ether was added dropwise with good stirring butylamine (6.05 g, 0.083 mole) in 40 ml. of ether. The reaction was stirred at room temperature overnight, then the reaction mixture was filtered, and the filtrate concentrated in vacuo. The residue was dissolved in fresh ether, washed with water, dried over MgSO4, and concentrated in vacuo to yield 2-methoxyethyl N-trifluoroacetyl-N-(bis(butylamino)phosphonomethyl)glycinate (4.0 g), ND =1.4572.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.ClS([N:28]=[C:29]=O)(=O)=O>CN(C=O)C.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:29]#[N:28])=[C:9]2[CH3:23])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1c(C#N)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 20 °C
Yield: 76.7 %

Procedure:
To a cold solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (750 mg, 2.28 mmol) in DMF (8 ml) and acetonitrile (8 ml) at -78° C., chlorosulfonyl isocyanate (200 μl, 2.28 mmol) was added. The reaction mixture was warmed to 20° C. over 4 hours, quenched by adding excess of water, and extracted with ethyl acetate. The organic fractions were washed with brine, dried (MgSO4), filtered and concentrated. The crude colorless liquid (0.77 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carbonitrile (620 mg, 77%) as a white solid: mp (DSC) 205° C. Anal Calc'd. for C19H15N2SFO2 : C, 64.39; H, 4.27; N, 7.90. Found: C, 64.11; H, 4.45; N, 7.60.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].O.[OH-].[Li+].C(O)C.O.O1CCCC1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18]2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Yield: 88.9 %

Procedure:
Prepared as described in example 5b) using 2-chloro-5-[4-[[(1,1-dimethylethoxy)-carbonyl]amino]-1-piperidinyl]-benzoic acid, ethyl ester (Example 6a, 0.17 g), lithium hydroxide monohydrate (0.88 ml of a 3M solution in water), 1:1 ethanol/water (7 ml) and tetrahydrofuran (1 ml) to give the subtitle compound as a solid (0.14 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc(C#N)cc2)c1

Procedure:
500 mg (2.18 mmol) of methyl 3-bromomethylbenzoate, 437 mg (2.40 mmol) of 4-hydroxybenzonitrile and 600 mg of potassium carbonate were stirred in dimethylformamide at room temperature for 1.5 hours. The reaction mixture was filtered through Celite, then treated by an ordinary method and purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23]1)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The product from Example 92B and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.27-1.35 (m, 2H), 1.39 (s, 9H), 1.55-1.65 (m, 12H), 2.06-2.11 (m, 2H), 2.62-2.67 (m, 2H), 3.19-3.30 (m, 2H), 3.45-3.54 (m, 2H), 8.56 (s, 1H). MS (ESI+) m/z 410 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][OH:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:18][N-:19][CH3:20].[CH3:21][N-:22][CH3:23].C[N-]C.C[N-]C.[Ti+4:30]>C1(C)C=CC=CC=1>[CH3:18][N-:19][CH3:20].[CH3:21][N-:22][CH3:23].[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][O:13][Ti+2:30])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: [Ti+4]
Reactant: CC1=C(C)C(c2ccccc2CO)C(C)=C1C
Agent: C[N-]C
Solvent: Cc1ccccc1
Product: CC1=C(C)C(c2ccccc2CO[Ti+2])C(C)=C1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzylalcohol (0.3 g, 1.3 mmol) in toluene (5.2 mL) was added dropwise a solution of tetrakis(dimethylamido)titanium (0.29 g, 1.3 mmol) in toluene (1.7 mL) at −30° C. The mixture was stirred for 30 min at room temperature and then at 110° C. for 5 hrs. The solvent was distilled off to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzyloxytitanium bis(dimethylamide) (0.30 g, yield 83.3%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[N+]=[N-]>CO.[Pd]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]([CH2:4][NH2:1])=[CH:14]2
Reactant: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1N1CCCCC1
Agent: [Pd]
Solvent: CO
Product: NCc1cc2cccc(Cl)c2nc1N1CCCCC1

Procedure:
3-(Azidomethyl)-8-chloro-2-(piperidin-1-yl)quinoline (30 mg, 0.1 mmol) was dissolved in MeOH (1 mL) and treated with 10% Pd—C (5 wt %) and the mixture was then stirred under H2 balloon over night. The mixture was filtered through a Celite™ pad followed by removal of solvents to give (8-chloro-2-(piperidin-1-yl)-quinolin-3-yl)methanamine as a colorless oil. N-((8-chloro-2-(piperidin-1-yl)-quinolin-3-yl)methyl)-9H-purin-6-amine was prepared according to Procedure H.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[OH:20]O.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][C:10]([CH3:19])([C:15]([F:18])([F:16])[F:17])[C:11]([F:12])([F:13])[F:14])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(SCC(C)(C(F)(F)F)C(F)(F)F)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)CC(C)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
To 1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene (4.5 g, 14.9 mmol) in acetic acid (15 mL) at ambient temperature, add with stirring aqueous hydrogen peroxide (15 mL, 30% in water) and stir for 1 h. Dilute the reaction with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (4.125 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([CH3:35])[C:33]=1O)[C:29]#[N:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:18][CH2:17]3)[CH2:14][O:15][C:33]3[C:32]([CH3:35])=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=3[CH3:25])[C:11]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: OCC(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: Cc1cc(C#N)cc(C)c1OCC(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared from 2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopropyl-ethanol, 3,5-dimethyl-4-hydroxybenzonitrile (commercially available), tri-n-butylposphine and N′N′N′N-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 60:40). The so-obtained solid was again chromatographed on a preparative HPLC system using a Phenomenex Gemini column eluting with a gradient of acetonitril and water (containing 5% formic acid). White foam (20%). MS (Turbo Spray): m/z=478.149 [M+H].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[I:10][C:11](=[C:24]([I:26])[I:25])[CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CN(C)C=O>[I:10][C:11](=[C:24]([I:26])[I:25])[CH2:12][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Reactant: COC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1CC(I)=C(I)I
Temperature: 10 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of 125 mg (1 mmole) of methyl pyrrole-2-carboxylate in 5 ml of dry N,N-dimethylformamide were added 590 mg (1 mmole) of 2,3,3-triiodoallyl-p-toluenesulfonate and 50 mg (1.2 mmoles) of powdery sodium hydroxide while cooling at 10° C. and the resulting mixture was stirred for one hour. The reaction mixture was extracted with ethyl acetate and water, the ethyl acetate layer was separated, washed with water and then dried. The ethyl acetate layer was concentrated under reduced pressure, the residual oily substance was allowed to stand with 1.0 ml of methanol, thereby separating a crystalline substance, 1-(2',3',3'-triiodoallyl)-2-methoxycarbonylpyrrole. It was then recovered by filtration. Yield 127 mg (23% yield), mp 88°-90° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH:17][C:3]1=2.[CH3:22]O.S(=O)(=O)(O)O>>[CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:3]1=2
Reactant: CN1Cc2ccccc2C(=O)c2ccc(CC(=O)O)cc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2c(c1)N(C)Cc1ccccc1C2=O

Procedure:
5,6-Dihydro-5-methyl-11-oxodibenz[b,e]azepine-3-acetic acid was esterified with methanol-sulfuric acid in a customary manner to afford methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-3-acetate having a melting point of 88.4°-90.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].Br[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:29])[C:26]=1[O:27][CH3:28])[CH:22]=[O:23]>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:19]3[CH:20]=[C:21]([CH:24]=[C:25]([F:29])[C:26]=3[O:27][CH3:28])[CH:22]=[O:23])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reactant: COc1c(F)cc(C=O)cc1Br
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)cc(F)c3OC)cc21
Yield: 12 %

Procedure:
The intermediate 3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-5-fluoro-4-methoxy-benzaldehyde was prepared in a similar manner to example 7a using 7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example 2b) and 3-bromo-5-fluoro-4-methoxy-benzaldehyde. 12% yield. 1H-NMR (300 MHz, CDCl3): 1.23 (t, J=7.0 Hz, 3 H), 1.33 (s, 6 H), 2.13 (s, 3 H), 2.53 (s, 2 H), 3.91 (s, 3 H), 4.01 (q, J=7.0 Hz, 2 H), 6.83 (s, 1 H), 7.19 (s, 1 H), 7.50 (d, J=1.8 Hz, 1 H), 7.66 (dd, J1=11.7 Hz, J2=2.1 Hz, 1 H), 9.91 (s, 1 H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[N:22][C:23]=3[C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:16])=[O:15])(=O)=O)=CC=1.[CH2:29]1[O:39][C:38]2[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][C:31]=2[O:30]1>O1CCCC1>[CH2:29]1[O:39][C:38]2[CH:37]=[CH:36][C:33]([CH2:34][NH:35][CH2:11][CH2:12][NH:13][S:14]([C:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[N:22][C:23]=4[C:24]([Cl:27])=[CH:25][CH:26]=3)(=[O:15])=[O:16])=[CH:32][C:31]=2[O:30]1
Reactant: Cc1ccc(S(=O)(=O)OCCNS(=O)(=O)c2ccc(Cl)c3ncccc23)cc1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: O=S(=O)(NCCNCc1ccc2c(c1)OCO2)c1ccc(Cl)c2ncccc12
Yield: 56.9 %

Procedure:
3.32 g of N-(2-paratoluenesulfonyloxyethyl)-8-chloro-5-quinolinesulfonamide was reacted with 30 ml of a tetrahydrofuran solution containing 3.41 g of 3,4-methylenedioxybenzylamine in a sealed vessel at 70° C. for 17 hours, and the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using, as an eluent, a mixture of methanol and chloroform (5% methanol) to thereby obtain 1.80 g of N-[2-(3,4-methylenedioxybenzylamino)ethyl]-8-chloro-5-quinolinesulfonamide (13) (yield: 57%)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:45][CH:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NC1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NC1CCOCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 40 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.07 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (38.2 μL, 0.348 mmol), tetrahydro-2H-pyran-4-amine (12.66 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide (14.3 mg, 0.028 mmol, 40%): LCMS=515.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.06-8.25 (2 H, m), 7.49-7.78 (7 H, m), 5.04-5.18 (1 H, m), 3.81-4.01 (2 H, m), 3.38-3.58 (2 H, m), 1.73-1.93 (2 H, m), 1.48-1.73 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.6 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10](=[O:12])[N:35]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[C:14](=[O:16])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C(=O)C1

Procedure:
A solution of 27 (547 mg, 2.35 mmol) and carbonyl diimidazole (837 mg, 5.16 mmol) in 4.7 mL of dry THF under a N2 atmosphere was refluxed for 5 minutes. Once the reaction cooled down to room temperature 4-fluorobenzyl amine (0.295 mL, 2.58 mmol) was added and the mixture was heated to reflux overnight. The reaction mixture was then concentrated and re-dissolved in EtOAc. The organic layer was washed with an aqueous 0.5 N HCl solution and the solvent was removed in vacuo. The product was purified by column chromatography eluting with CH2Cl2 to provide clean product 28 as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 4.39 (s, 4H), 4.92 (s, 2H), 6.99 (t, 2H, J=9 Hz), 7.40 (dd, 2H, J=5, 9 Hz); 13C NMR (75 MHz, CDCl3) δ 28.1, 42.0, 47.1, 82.3, 115.2, 115.5, 131.1, 131.2, 132.0, 153.0, 162.7 (d, J=245 Hz), 168.0; 19F NMR (282.6 MHz, CDCl3) δ 62.5; EI MS (m/z) 340.5 [M+Na].
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:30])([CH3:29])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4([CH2:26][C:27]#[N:28])[CH2:25][NH:24][CH2:23]4)[CH:21]=3)=[C:11]2[CH:10]=[CH:9]1.Cl[C:32]1[N:33]=[CH:34][C:35]([C:38]([NH:40][C@H:41]([CH:43]2[CH2:45][CH2:44]2)[CH3:42])=[O:39])=[N:36][CH:37]=1.C(N(CC)C(C)C)(C)C>>[C:27]([CH2:26][C:22]1([N:20]2[CH:21]=[C:17]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[N:8]([CH2:7][O:6][CH2:5][CH2:4][Si:3]([CH3:29])([CH3:2])[CH3:30])[CH:9]=[CH:10][C:11]=34)[CH:18]=[N:19]2)[CH2:23][N:24]([C:32]2[N:33]=[CH:34][C:35]([C:38]([NH:40][C@H:41]([CH:43]3[CH2:45][CH2:44]3)[CH3:42])=[O:39])=[N:36][CH:37]=2)[CH2:25]1)#[N:28]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Reactant: C[C@H](NC(=O)c1cnc(Cl)cn1)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C1CC1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
A mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (200 mg, 0.4 mmol) (Example 40, Step 3), 5-chloro-N-[(1S)-1-cyclopropylethyl]pyrazine-2-carboxamide (100 mg, 0.46 mmol) in N,N-diisopropylethylamine (0.7 mL, 4 mmol) in a sealed vial was stirred at 120° C. for 1.5 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford the desired product (0.23 g).