Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[S:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:19])[C:17]=2[N:18]=1.[OH:20]O>C(Cl)Cl.C[Re](=O)(=O)=O>[Cl:9][C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:10]1[S:11][C:12]2[CH:13]=[N+:14]([O-:20])[CH:15]=[C:16]([F:19])[C:17]=2[N:18]=1
Reactant: Fc1cncc2sc(-c3c(Cl)cc(I)cc3Cl)nc12
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nc(-c3c(Cl)cc(I)cc3Cl)sc2c1
Yield: 45 %

Procedure:
To a solution of 2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine (5.3 g, 12.6 mmol) in DCM (100 mL) under a nitrogen atmosphere was added methyltrioxorhenium(VII) (313 mg, 1.3 mmol) followed by 30% aqueous hydrogen peroxide (2.6 mL, 25.1 mmol). The reaction mixture was stirred at room temperature for 48 hours with a further two additions of methyltrioxorhenium(VII) (313 mg, 1.3 mmol) and 30% aqueous hydrogen peroxide (2.6 mL, 25.1 mmol) added over this period. The precipitate obtained was collected by filtration and the filtrate was partitioned between water. The aqueous layer was extracted with DCM (×2). The combined organic phases were washed with a saturated solution of NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The resultant residue was combined with the previously filtered solid and was purified by column chromatography on silica gel eluting with 0-90% EtOAc in petroleum ether (40-60° C.), followed by 0-10% MeOH in DCM to afford the title compound as a white solid (2.5 g, 45% yield). LCMS (Method D): RT=3.36 min, m/z: 441 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[CH:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH:17]1([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)c(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(C2CC2)c(-c2ccccc2)c1
Yield: 17.5 %

Procedure:
In a schlenck tube, a mixture of 2-chloro-5-nitro-3-phenylpyridine (described in Intermediate 3 (step B)) (1.43 mmol, 0.4 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.59 mmol, 0.29 ml), PdCl2dppf.DCM (0.14 mmol, 0.12 g), Cs2CO3 (4.3 mmol, 1.4 g) in a dioxane/water 4:1 mixture (6.5 ml) was heated at 100° C. for 16 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 2-cyclopropyl-5-nitro-3-phenylpyridine (0.06 g, 17% of yield) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:27])=[N:24][O:25][N:26]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:23]1[C:22]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[N:26][O:25][N:24]=1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1nonc1-c1ccc(Cl)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)Nc2nonc2-c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
200 mg (0.85 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid and 167 mg (0.85 mmol) of 4-(4-chlorophenyl)-1,2,5-oxadiazol-3-ylamine are dissolved in 24 ml of CH2Cl2 at RT and treated with 0.12 ml (0.85 mmol) of triethylamine, 21 mg (0.17 mmol) of DMAP and 1814 mg (1.28 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 30 h at RT and subsequently washed twice with in each case 5 ml of water. The organic phase is dried over Na2SO4 and evaporated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield 140 mg (36%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1.[CH:24](=O)[CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH3:26])[CH2:10][CH:9]=2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1
Reactant: Cc1ccc(C2=CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCN1CC=C(c2ccc(C)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a solution of 4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine (70 mg, 0.23 mmol) produced in Example (104f) in tetrahydrofuran (2 mL) were added propionaldehyde (15.7 mg, 0.27 mmol), sodium triacetoxyborohydride (72 mg, 0.34 mmol) and acetic acid (27 mg, 0.45 mmol), followed by stirring for 12 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 63 mg of 4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.C(O)C>[Pd].C(N(CC)CC)C>[C:5]1([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)c[nH]1
Reaction time: 3 h
Yield: 78.9 %

Procedure:
4-(4-Chlorophenyl)pyrrole-2-carboxylic acid (0.6 g.) was hydrogenated over 200 mg. of 5% Pd/C in 50 ml. of ethanol for approximately 16 hours at 50 p.s.i. An additional 200 ml. of catalyst and 1 ml. of triethylamine was added and hydrogenation continued for 3 hours at 50 p.s.i. The catalyst was recovered by filtration, and the mother liquor concentrated to dryness to yield 4-phenylpyrrole-2-carboxylic acid [400 mg., m.p. 226°-228° C. (dec.), m/e 187]. For analysis, the product was recrystallized from acetone/hexane [240 mg., m.p. 227°-229° C. (dec.)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C:53](=[O:64])[CH2:54][CH:55]([NH2:63])[C:56]1[CH:61]=[CH:60][C:59]([OH:62])=[CH:58][CH:57]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[OH:62][C:59]1[CH:60]=[CH:61][C:56]([CH:55]([NH:63][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[CH2:19]2)=[O:25])[CH2:54][C:53]([O:52][CH3:51])=[O:64])=[CH:57][CH:58]=1
Reactant: COC(=O)CC(N)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
490.75 mg (1.33 mmol) (3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (Bioorg. Med. Chem. 13 (2005) 4343-4352, Compound 10) were suspended in 8 ml N,N-dimethylformamide and cooled to 0° C. 0.545 g (1.43 mmol) HATU, a solution of 200.0 mg (1.0 mmol) 3-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester in 12 ml N,N-dimethylformamide and 0.53 ml (3.07 mmol) N-ethyl-diisopropylamine were added. The mixture was stirred at 0° C. for 5 minutes and at room temperature for 24 hours. 20 ml water were added and the mixture extracted with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum. Chromatography over 28 g basic silica gel (dichloromethane/ethanol 100/0-95/5-90/10-80/20) gave 465 mg (83%) tert-butyl 4-[3-((3R)-3-{[1-(4-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[S:17]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)(=[O:20])(=[O:19])[NH2:18]>>[S:17]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:16][C:13]2[CH:14]=[CH:15][C:10]([S:9][S:8][C:5]3[CH:4]=[CH:3][C:2]([N:1]=[CH:25][C:24]4[CH:27]=[CH:28][C:21]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:22][CH:23]=4)=[CH:7][CH:6]=3)=[CH:11][CH:12]=2)=[CH:23][CH:22]=1)(=[O:20])(=[O:19])[NH2:18]
Reactant: Nc1ccc(SSc2ccc(N)cc2)cc1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Product: NS(=O)(=O)c1ccc(C=Nc2ccc(SSc3ccc(N=Cc4ccc(S(N)(=O)=O)cc4)cc3)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using bis(4-aminophenyl) disulfide [prepared as described in step (i) above] and 4-sulfamoylbenzaldehyde as starting materials, the title compound was obtained as a slightly yellow powder (yield 58%), melting at 200-230° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](#[N:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CCCCC>[C:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][C:20](=[NH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1ccccc1Sc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: O
Product: N=C(Nc1ccccc1Sc1ccccc1)c1ccccc1
Yield: 69.4 %

Procedure:
Procedure as described for Amidine I using the following amounts and modifications: 10.06 g of 2-phenylthioaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.20 mL of benzonitrile (51.0 mmol). After refluxing overnight, the solution was green-brown. Addition of water yielded a light brown solution with suspended solid. Solution was taken to dryness, resuspended in 75 mL of pentane, filtered, washed with 10 mL of pentane and dried in vacuo yielding 10.56 g (69%) of beige powder. NMR (400 MHz, C6D6): 7.76 (d, 2H), 7.42 (d, 2H), 7.31 (d, 1H), 7.1-6.8 (m, 8 H), 6.78(t, 1H), 4.08 (s, 2H).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH2:9]([CH:16]([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.CN(C)C=O>[NH2:7][C:6]([NH2:8])=[NH:5].[S:23](=[CH:22][CH:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:25])=[O:24]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C=S(=O)=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
5.06 g (28 mmol) of guanidine carbonate are added at -10° to a solution of 4.73 g (16.2 mmol) of crude ethyl 2-benzyl-3-chlorosulphonyl-propionate, prepared according to the procedure described in EPA 0236734, in 150 ml of methylene chloride and 40 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight and thereafter evaporated. The residue is partitioned between methylene chloride and water, the aqueous phase is separated, evaporated under reduced pressure and the residue obtained is chromatographed on 50 g of silica gel using a 9:1 to 1:1 mixture of water and methanol as the eluent. The product obtained is recrystallized from a mixture of methanol and ether. There are obtained 3.29 g of ethyl (RS)-α-(sulphonylmethyl)hydrocinnamate guanidine salt as colourless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:49][C:50]1[CH:51]=[C:52]([CH2:56][CH2:57][C:58](O)=[O:59])[CH:53]=[CH:54][CH:55]=1>C1COCC1>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][O:14][C:58](=[O:59])[CH2:57][CH2:56][C:52]3[CH:53]=[CH:54][CH:55]=[C:50]([OH:49])[CH:51]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1F
Reactant: O=C(O)CCc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2COC(=O)CCc2cccc(O)c2)cc1F
Reaction time: 0.17 h

Procedure:
To a solution of the alcohol from Step F (79.7 mg, 0.345 mmol) and triphenylphosphine (90.0 mg, 0.345 mmol) in 0.5 mL of THF was added a solution of diethylazodicarboxylate (0.054 mL, 0.345 mmol) and 3-(3-hydroxyphenyl)propionic acid (57 mg, 0.34 mmol) in 0.5 mL of THF. After 10 minutes, HPLC analysis indicated 60% conversion. Additional triphenylphosphine (45 mg, 0.17 mmol) and diethylazodicarboxylate (0.027 mL, 0.17 mmol) were added, and the reaction was stirred for 10 more minutes. The solution was concentrated in vacuo, then purified by silica gel chromatography (3% MeOH/CH2Cl2) to provide the desired product as a white foam.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)[CH3:8].Br[CH2:21][CH2:22]Br>CN(C=O)C>[CH2:7]([O:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:21][CH2:22][O:18][C:13]=2[CH:12]=1)=[O:19])[CH3:8]
Reactant: BrCCBr
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 mL) were added 3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane (54.3 g, 0.29 mol) at room temperature. The resulting mixture was stirred at 80° C. overnight and then poured into ice-water. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (200 mL×3) and brine (100 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column (petroleum ether/ethyl acetate 50:1) on silica gel to obtain 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1H NMR (300 MHz, CDCl3) δ 7.53 (dd, J=1.8, 7.2 Hz, 2 H), 6.84-6.87 (m, 1 H), 4.22-4.34 (m, 6 H), 1.35 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Rh]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
A solution of (2R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-phenylpentanoic acid (Syn. Lett.; 1998; 637-639) (10.00 g, 34.2 mmol) in acetic acid (120 ml) was treated with 5% Rhodium on alumina catalyst, pressurised to 60 psi with hydrogen in a sealed vessel and stirred at room temperature for 17 hours. The mixture was filtered through a pad of Arbocel® and the solvent was removed from the filtrate under reduced pressure. The residue was azeotroped from toluene to afford the title compound (7.53 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:31]1[CH2:30][CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:23][CH:24]=2)[CH2:33][CH2:32]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1ccc(C2=CCNCC2)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC=C(c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized 2-isopropoxy-5-methanesulfonyl-benzoic acid and 4-(4-Methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridine. MS (m/e): 495.4 (M+NH4+, 100%)
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[C:32]3[CH2:34][NH:35][CH2:36][CH2:37][C:31]3=[N:30][C:29]=2[NH:38][CH:39]([CH3:41])[CH3:40])[CH2:24][CH2:23]1.C=O>CO>[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:33]=[C:32]3[CH2:34][N:35]([CH3:2])[CH2:36][CH2:37][C:31]3=[N:30][C:29]=2[NH:38][CH:39]([CH3:41])[CH3:40])[CH2:26][CH2:27]1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C)CC2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (12.3 mg, 0.058 mmol) was added to a solution of DIPEA (10 μL, 0.058 mmol), 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15.0 mg, 0.029 mmol) and formaldehyde (2 μL, 0.029 mmol) in MeOH (290 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (12.3 mg, 80%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (d, J=6.6 Hz, 6H), 1.90-2.00 (m, 2H), 2.07-2.16 (m, 2H), 2.96-3.05 (m, 3H), 3.08 (br s, 4H), 3.33-3.42 (m, 2H), 3.43-3.85 (m, 2H), 4.14-4.38 (m, 3H), 4.44-4.51 (m, 1H), 6.84-6.91 (m, 1H), 6.95-7.02 (m, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 418.3.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[C:14]([NH:18][NH2:19])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:14]([NH:18][NH:19][C:8](=[O:10])[C:7]1[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=1[O:11][CH3:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1nccc(I)c1C(=O)O
Reactant: CC(C)(C)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nccc(I)c1C(=O)NNC(C)(C)C
Yield: 86 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (3.00 g) obtained in Step C of Example 6, tert-butylhydrazine hydrochloride (1.61 g), DIEA (5.63 mL), EDCI hydrochloride (2.47 g) and HOBt (1.74 g) in DMF (100 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.23 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=[O:33].CO>[Pd]>[CH:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:33]
Reactant: O=CO
Reactant: Fc1ccc(-c2ncn(C3CCN(Cc4ccccc4)CC3)c2-c2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=CN1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C

Procedure:
1-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (100 mg;prepared in Example 40) was dissolved in 10% formic acid/methanol under argon and palladium black (100 mg) mixed in 10% formic acid/methanol was added. The reaction was stirred under argon at room temperature for sixteen hours. The reaction mixture was evaporated and the residue mixed in H2O/ethyl acetate and the pH taken to 10. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were evaporated and the residue was flash chromatographed (silica gel/methylene chloride/methanol) to yield the title compound, an off-white solid. ES (+) MS m/e=351 (MH+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:41]5[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 36.1 %

Procedure:
Following general procedure II, tert-butyl(1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]pyridin-2-yl}piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 mg, 0.24 mmol) to afford crude product (45 mg) which was carried forward without any purification: ESI MS m/z 623 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:7]=1.CCO.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(OCc2ccccn2)nn1
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(OCc3ccccn3)nn2)c(C)c1
Yield: 58 %

Procedure:
3-Chloro-6-(pyridin-2-ylmethoxy)pyridazine (Example 15a) (221 mg, 1 mmol) was dissolved in toluene (10 mL), EtOH (2 mL), and water (1.5 mL). Then 2,4-dimethylphenylboronic acid (150 mg, 1 mmol) was added, followed by K2CO3 (276 mg, 2 mmol) and the mixture was degassed using argon stream. Tetrakis(triphenylphosphine)palladium (232 mg, 0.2 mmol) was added under argon and the mixture was refluxed overnight. The solvents were removed under vacuum and a residual solid was extracted with EtOAc, and successively washed with water and brine dried over MgSO4 filtered and evaporated. The crude material was purified on silica gel (Eluent: 50% EtOAc in hexanes) to give 3-(2,4-Dimethylphenyl)-6-(pyridin-2-ylmethoxy)pyridazine (169 mg, 58%) as a white solid. 1H NMR (300 MHz, dMSO): δ 2.26 (s, 3H), 2.32 (s, 3H), 5.62 (s, 2H), 7.13-7.15 (m, 2H), 7.28-7.40 (m, 2H), 7.55-7.56 (d, 1H), 7.78-7.84 (m, 2H), 8.58-8.60 (d, 1H); MS (M+H, 292).