Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
4-[4-(Trifluoromethoxy)phenoxy]piperidine (2.61 g), benzyl 4-bromophenyl ether (2.63 g), palladium (II) acetate (0.67 mg), Tri-tert-butyl phosphonium tetraphenyl borate (1.57 mg), sodium tert-butoxide (1.06 g) and toluene (13 mL) were placed in a vessel and heated to reflux for 6 hr under Ar. The reaction mixture was then cooled to room temperature and water (100 mL) and ethyl acetate (100 mL) were added. The organic material was taken up in ethyl acetate. The organic layer was washed three times with water (100 mL×3). The organic layer was filtered to remove harz and then the organic layer was condensed under reduced pressure to afford 4.36 g (98.4% yield) of a pale yellow crystal target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[OH:13].Cl[CH2:20][C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[O:13][CH2:20][C:21](=[O:23])[CH3:22]
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)c(O)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl

Procedure:
21.56 g of 4-(2,4-dichlorophenoxy)-3-hydroxybenzonitrile, 14.2 g of chloroacetone, 12.8 g of potassium carbonate and 170 mg of potassium iodide are dissolved in 300 ml of acetone and boiled under reflux for 5 h. After cooling, the precipitate is filtered, concentrated by evaporation, redissolved in ethylacetate and washed with a 1N aqueous solution of sodium hydroxide, water, a 1N aqueous solution of hydrogen chloride and finally with brine. The organic phase is dried over magnesium sulfate and evaporated. The residue is recrystallized from ethylacetate/hexane to yield 4-(2,4-dichlorophenoxy)-3-(2-oxopropoxy)-benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:28]([O:29][CH3:30])[CH3:27])=[O:13])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 65 °C
Yield: 91 %

Procedure:
To a solution of 5-bromo-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (VIII) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65° C. under nitrogen. The solution was cooled to room temperature and N,O-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65° C. under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10% HCl solution, a saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (IX) as a white solid (260 mg, 0.91 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01 Hz, 1 H), 8.67 (d, J=3.01 Hz, 1 H); ESIMS Found for C9H9BrN4O2 m/z 285.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:34])[N:22]=1>>[F:18][C:6]1[CH:5]=[C:4]([NH:19][C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[N:24]=[C:23]([NH2:34])[N:22]=2)[CH:3]=[C:2]([F:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Product: Nc1nc(Nc2cc(F)c(Oc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccc(F)cc2)n1

Procedure:
Analogously to example 25, the title compound is synthesized from 100 mg (0.36 mmol) of [3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XXXIV) and 110 mg (0.36 mmol) of 4-chloro-6-(4-fluorophenyl)pyrimidine-2-amine (from example LIX). Purification by preparative HPLC gives the product.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH:8]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]([OH:11])[CH3:10])([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[CH3:1][C:2]([Si:5]([CH3:21])([CH3:22])[O:6][CH2:7][C@H:8]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9](=[O:11])[CH3:10])([CH3:3])[CH3:4]
Reactant: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)C(C)=O
Reaction time: 18 h
Yield: 81.8 %

Procedure:
A mixture of (10c), (2.30 g, 6.94 mmol) and pyridinium dichromate (10.62 g, 28.2 mmol) in 20 mL of N,N-dimethylformamide is stirred under argon for 18 h. The reaction mixture is diluted with 100 mL of water and extracted with ethyl acetate (3×40 mL). The organic layer is separated, washed with water and brine, dried and evaporated to give 1.87 g of a residual brown liquid. The liquid is purified by chromatography using 1:6 ethyl acetate/hexane to give 997 mg of the desired product as an oil. NMR δ 0.83 (s, 9 H), 1.61 (m, 2 H), 2.22 (t, 2 H), 2.23 (s, 3 H), 3.82 (dd, 1 H), 4.09 (dd, 1 H), 4.57 (m, 1 H), 6.42 (brd, 1 H); MS (FAB) m/z 330 (M+H calc'd for C17H36NO3Si 330).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([Br:15])[CH:3]=1.C([Li])CCC.CCCCCC.[CH3:27][S:28]SC>C1COCC1.C(OCC)(=O)C>[Br:15][C:4]1[CH:3]=[C:2]([S:28][CH3:27])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=1
Reactant: Brc1cc(Br)c2c(c1)oc1ccccc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1cc(Br)cc2oc3ccccc3c12
Temperature: -50 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
A solution of 1,3-dibromodibenzofuran 18 (0.500 g, 1.54 mmol) in THF (53 ml) was cooled to -70° C. and a solution of n-butyllithium in hexane (2.2M, 0.84 ml, 1.8 mmol) was added dropwise. The resulting red solution was allowed to warm to -50° C. over 30 minutes. Methyl disulfide (0.162 ml, 1.84 mmol) was added and the solution was allowed to warm to -10° C. After stirring for 20 minutes, the solution was poured into ethyl acetate and washed successively with 1N NaOH, H2O, and brine. Drying over MgSO4 and evaporation gave a tan solid which was purified by flash chromatography through 40 g of silica gel (10% CH2Cl2 -hexane) to yield 394 mg (87%) of the title compound as a white powder.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.I[CH:10]([CH3:12])[CH3:11].[OH-].[K+].[OH-].[Na+]>C(O)C.O>[CH3:11][CH:10]([O:7][C:3]1[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][CH:4]=1)[CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)I
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cccc(O)c1
Yield: 19.5 %

Procedure:
To a solution of 1,3-benzenediol (8 g, 72.7 mmol) and 2-iodopropane (12 g, 70.6 mmol) in ethanol (100 mL preheated at reflux) was added a solution of KOH (83%, 5.3 g, 77.6 mmol) in water (20 mL) over a period of 30 minutes. The mixture was refluxed for 3 hours and poured into NaOH (1N, 100 mL). The resulting mixture was extracted with ethyl acetate (3 times 50 mL) and the aqueous layer was acidified with 10% HCl to adjust the pH=5 and extracted with ethyl acetate (3 times 50 mL). The combined extracts were washed with brine (50 mL), dried and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE:EtOAc=5:1) to afford the title compound as a colourless oil (2.1 g).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)#[N:3].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[N:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=CCCCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NN=CCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a mixture of 4-cyanophenylhydrazine HCl (3.44 g, 20.3 mM) and 6-chlorohexanal (2.5 g, 18.6 mM) in toluene (30 mL) was added triethylamine at 0° C. (2.82 mL, 20.3 mM). The mixture was allowed to stir for 2 hours at ambient temperature. The mixture was filtered and the resultant filter cake was washed with toluene. The combined filtrate was concentrated under vacuum to give 4.92 g of a crude product, which was purified using conventional methods to yield 4.16 g (89.6%) of 4-(2-(6-chlorohexylidene)hydrazinyl)benzonitrile as a mixture of cis:trans isomers (ratio 5:1). NMR (400 MHZ, CDCl3): 7.6-6.6 (6H, (4H, dd-aromatic; 1H (m)-NH, 1H (t)-N═CH-t)), 3.57 (2H (t), CH2Cl), 2.2-2.4 (2H (m), ═CH—CH2), 1.75-1.90 (2H (m), CH2Cl—CH2), 1.49-1.65 (4H (m), CH2—CH2); m/z: 250 [M+H]+, calcd for [C13H16ClN3+H]+ 250.10.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17](O)=[O:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1.C1C=CC2N(O)N=[N:32]C=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[S:13][C:14]([C:17]([NH2:32])=[O:18])=[CH:15][N:16]=2)[CH2:10][CH2:11]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxylic acid (14.5 g, 39 mmol), HOBt (5.3 g, 39 mmol)), HATU (23.7 g, 62 mmol) and NH4Cl (6.3 g, 117 mmol) in DMF (200 mL) at room temperature was added Hünig's base (34 mL, 195 mmol) over about 15 min. The mixture was stirred at room temperature overnight. After dilution with water, the mixture was extracted twice with EtOAc. The EtOAc extracts were combined, washed with 0.5 N NaOH (2×), diluted brine (1×), dried (Na2SO4) and concentrated. The residue was triturated with Et2O/hexanes (1:1) to give the title compound as a pale yellow solid. 1H NMR (500 MHz, acetone-d6): δ7.79 (s, 1H), 7.67-7.61 (m, 2H), 7.38 (d, 1H), 7.12 (t, 1H), 5.02 (s, 1H), 3.76 (t, 2H), 3.71-3.67 (m, 2H), 2.16 (t, 2H), 2.00-1.94 (m, 2H).
Reaction SMILES: C([C:4]1[NH:8][C:7]([C:9]([O:11]C)=[O:10])=[C:6]([Cl:13])[CH:5]=1)(=O)C.CO.[Li+].[OH-].C1C[O:21][CH2:20][CH2:19]1>>[C:20]([C:5]1[C:6]([Cl:13])=[C:7]([C:9]([OH:11])=[O:10])[NH:8][CH:4]=1)(=[O:21])[CH3:19]
Reactant: C1CCOC1
Reactant: COC(=O)c1[nH]c(C(C)=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1c[nH]c(C(=O)O)c1Cl
Temperature: 60 °C
Yield: 67 %

Procedure:
Methyl 5-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.034 g, 0.169 mmol) was dissolved in THF (1 mL), methanol (1 mL) and 1N LiOH (1 mL). The reaction mixture was heated to 60° C. and stirred. The reaction mixture was evaporated and purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.033 g, 67%) as an impure product which was used with no further purification. LCMS: m/z 187.9 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[N:10]([N:14]([C:30](=[O:32])[CH3:31])[C@H:15]([C:20]([NH:22][C@H:23]([C:27]([OH:29])=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:21])[CH2:16][C:17](=[O:19])[OH:18])[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2]>CO>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[NH:12][C:11](=[O:13])[N:10]([N:14]([C:30](=[O:32])[CH3:31])[C@H:15]([C:20]([NH:22][C@H:23]([C:27]([OH:29])=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:21])[CH2:16][C:17](=[O:18])[OH:19])[C:9]2=[O:33])=[CH:34][CH:35]=1
Reactant: CC(=O)N([C@@H](CC(=O)O)C(=O)N[C@H](C(=O)O)C(C)C)N1C(=O)NC(=Cc2ccc(C#N)cc2)C1=O
Solvent: CO
Product: CC(=O)N([C@@H](CC(=O)O)C(=O)N[C@H](C(=O)O)C(C)C)N1C(=O)NC(Cc2ccc(CN)cc2)C1=O
Reaction time: 12 h

Procedure:
400 mg of (5-(4-cyanobenzylidene)-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-valine are dissolved in 60 ml of methanol. After addition of 50 mg of 10% strength Pd-on-charcoal, hydrogenation is carried out at room temperature for 12 hours, the catalyst is filtered off, the filtrate is concentrated and the product is freeze-dried.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:9]([Cl:27])=[CH:8][C:7]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[CH:12][C:11]=3[Cl:13])[C:16]2=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1C(Cc2c(Cl)cc(-c3ccsc3)cc2Cl)CCN1C1CCCCC1

Procedure:
Using the method of Example 81 and using 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.485 g, 3.31 mmol), thiophene-3-boronic acid (1.2 g, 9.39 mmol) tetrakis(triphenylphosphine)palladium (0.362 g, 0.3.13 mmol), dimethoxyethane (15 mL) and sodium carbonate (2M, 5.5 mL) gives the title compound. Purify the crude material over silica gel (4/1 hexane in ethyl acetate) to yield 1.109 g (87%) of the title compound: mass spectrum (m/z): 410(M+2).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH:21]=3)=[C:11]([F:29])[CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.C1(C)C(S([NH:48][N:49]=[C:50]([CH3:54])[CH:51](Cl)Cl)(=O)=O)=CC=CC=1>C(OCC)(=O)C>[CH2:22]([N:19]1[CH2:18][CH:17]=[C:16]([C:12]2[C:13]([F:15])=[CH:14][C:9]([N:5]3[CH2:4][C@H:3]([CH2:2][N:1]4[CH:51]=[C:50]([CH3:54])[N:49]=[N:48]4)[O:7][C:6]3=[O:8])=[CH:10][C:11]=2[F:29])[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC[C@H]1CN(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Reactant: CC(=NNS(=O)(=O)c1ccccc1C)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(Cc5ccccc5)CC4)c(F)c3)C(=O)O2)nn1
Yield: 46.7 %

Procedure:
(5S)-5-(Aminomethyl)-3-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-diflurophenyl]-1,3-oxazolidin-2-one (Intermediate 54) (3.20 g, 8.01 mmol) was reacted with diisopropylethylamine (5.60 ml, 32.04 mmol) and 1,1-dichloroacetone toluenesulfonylhydrazone (2.8 g, 9.6 mmol) as described for Example 3. Chromatography on silica gel with ethyl acetate gave 1.74 g of the title product.
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:19]=2[S:18]3)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>O>[N:38]1([CH2:37][CH2:36][O:27][C:25]2[CH:24]=[CH:23][C:20]3[N:21]4[CH:22]=[C:15]([C:12]5[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=5)[N:16]=[C:17]4[S:18][C:19]=3[CH:26]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
This product was prepared according to J. Med. Chem. 2009, 52, 7808-7816 with some modifications. A mixture of 2-amino-1,3-benzothiazol-6-ol (2.0 g, 12.18 mmol) and 2-bromo-4′-nitroacetophenone (2.97 g, 12.18 mmol) in IPA (40 ml) was heated to reflux for 24 h. The reaction mixture was then cooled to 0° C. and the resulting precipitate was filtrated and washed with IPA to afford 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol (65% c.y.). To a DMF (52 ml) solution of 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol was added potassium carbonate (2.94 g) and 4-(2-chloroethyl)morpholine hydrochloride (1.97 g). The reaction mixture was heated to 85° C. and stirred at the same temperature for 48 h. Then it was poured into water (100 ml), filtered and washed with water and ethyl ether to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole (86% c.y.). A mixture of 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole and ammonium chloride (0.77 g) in ethanol (50 ml) was heated to reflux, and then iron powder (3.0 g) was added. The mixture was refluxed for 5 h and then immediately filtered though Celite and washed with hot ethanol. The filtrate was concentrated, neutralized with saturated NaHCO3 solution and extracted with DCM. The organic solution was dried with Na2CO3 and the solvent was removed under reduced pressure to afford the desired product [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b]benzothiazol-2-yl]aniline (32% c.y.).
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12]O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].S(Cl)([Cl:16])=O.C1COCC1>ClC(Cl)C>[Cl:16][CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)C1CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)C1CCN(CCCl)CC1
Temperature: 74 °C
Yield: 59.3 %

Procedure:
A mixture of 2-(4-(methylsulfonyl)piperidin-1-yl)ethanol (620 mg, 2.99 mmol) and thionyl chloride (1.092 mL, 14.95 mmol) in dichloroethane (5 mL) was heated up at 74° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to provide the crude, to the crude was added THF (10 mL), the grey precipitate was observed and collected. The solid was dried under vacuum for 20 hour to provide the desired product as grey solid (400 mg, 59%). LCMS: m/e 226.1 (M+H)+, 1.00 min (method 6).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([F:12])[CH2:11][O:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:21])([F:20])[C@@H:17]([OH:19])[CH3:18]>>[F:12][C:8]1([C:7]2[C:2]([O:19][C@@H:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][O:10][CH2:9]1
Reactant: N#Cc1cc(Cl)c(C2(F)COC2)cn1
Reactant: C[C@H](O)C(F)(F)F
Product: C[C@H](Oc1cc(C#N)ncc1C1(F)COC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carbonitrile (Example 131a) and (S)-1,1,1-Trifluoro-propan-2-ol (CAN 3539-97-7) as starting materials and isolated (1.66 g, 61%); MS (ESI, m/z): 291.4 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:34])([CH3:33])[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH3:33][C:19]([NH:34][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:18])[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1oc(-c2ccccc2)nc1CC(C)(C)N
Product: Cc1oc(-c2ccccc2)nc1CC(C)(C)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 1,1-dimethyl-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamine (57.2 mg, 0.32 mmol) as starting materials and isolated (75 mg, 73.6%) as white solid; LC-MS (UV peak area, ESI) 92.82%, 446.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>[O-2].[O-2].[Mn+4].O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1
Reactant: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (745 mg, 1.61 mmol, Intermediate 9: step a) was added 1,4-dioxane (35 mL), producing a suspension at room temperature. Warming to 45° C. formed a homogeneous solution. Then manganese dioxide (719 mg, 8.28 mmol) was introduced and the mixture was heated to 85° C. After 2 hours, the contents were filtered through Celite® while still warm and rinsed with THF. The solution was concentrated and the crude material was triturated with Et2O to provide the title compound as a bright white solid. The mother liquors were re-purified by concentrating and re-triturating with Et2O to afford additional title compound.
Reaction SMILES: O1CCCC1.Cl.[CH3:7][O:8][C:9](=[O:12])[CH2:10][NH2:11].[S:13]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15][S:14]1.P(C#N)(OCC)(OCC)=O>CN(C)C=O.C(N(CC)CC)C>[S:13]1[CH2:17][CH:16]([C:18]([NH:11][CH2:10][C:9]([O:8][CH3:7])=[O:12])=[O:19])[CH2:15][S:14]1
Reactant: O=C(O)C1CSSC1
Reactant: COC(=O)CN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)C1CSSC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.7 %

Procedure:
5 ml of anhydrous tetrahydrofuran, 1.01 ml of triethylamine and 398 mg of glycine methyl ester hydrochloride were added to 5 ml of a solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, and 0.55 ml of diethyl cyanophosphate was then added to the resulting mixture, whilst the ice-cooling, after which the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was left to stand at room temperature overnight, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was then removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 1:2 by volume mixture of ethyl acetate and hexane, to obtain 54 mg of the title compound as pale yellow crystals, melting at 73 to 75° C.