Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)(=O)C1C=CC=CC=1.CO.[OH-].[Na+].Cl>O>[F:29][C:28]([F:30])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH2:18][CH2:17][O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[OH:9])=[O:32])=[CH:23][CH:24]=1
Reactant: O=C(NCCCOc1ccccc1OC(=O)c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCCCOc1ccccc1O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a mixture of 0.87 g of 3-ethyl-5-methyl-4-(3-(4-(trifluoromethyl)benzamido)propyloxyphenyl benzoate and 10 ml of methanol was added a mixture of 0.16 g of sodium hydroxide and 2 m of water, while stirring at 0° C. After stirring at room temperature for 24 hours, the reaction mixture was made weak acidic by the addition of 10% hydrochloric acid, and extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.66 g of 3-ethyl-5-methyl-4-(3-(4-(trifluoromethyl)benzamido)propyloxyphenol (94% yield).
Reaction SMILES: COC([C:5]1[N:6]=C[O:8][C:9]=1[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=O.[ClH:16]>>[ClH:16].[NH2:6][CH2:5][C:9](=[O:8])[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ncoc1Cc1cccs1
Agent: Cl
Product: NCC(=O)Cc1cccs1
Temperature: 95 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
2.23 g 5-Thiophen-2-ylmethyl-oxazole-4-carboxylic acid methyl ester were suspended in 80 ml 6 N hydrochloric acid and stirred for 5 hours at 95° C. The solvent was removed at 30° C. under vacuum and the residue was suspended in ethylacetate, filtered and dried to yield 1.52 g (79%) 1-amino-3-thiophen-2-yl-propan-2-one hydrochloride; MS (ISP): m/e=156 (M+H+).
Reaction SMILES: CO.Cl.C[C@@H]1O[C@@H](O[C@H]2[C@H]([O:18][C@@H:19]3[C@:39]([CH2:41][OH:42])([CH3:40])[C@H:38]4[C@@:22]([CH3:51])([C@@H:23]5[C@@:35]([CH3:43])([CH2:36][CH2:37]4)[C@@:34]4([CH3:44])[C@@H:26]([C@@H:27]6[C@@:31]([C:45]([OH:47])=[O:46])([CH2:32][CH2:33]4)[CH2:30][CH2:29][C@H:28]6[C:48]([CH3:50])=[CH2:49])[CH2:25][CH2:24]5)[CH2:21][CH2:20]3)OC[C@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O>O>[CH3:50][C:48]([C@H:28]1[C@@H:27]2[C@@H:26]3[C@@:34]([CH3:44])([CH2:33][CH2:32][C@@:31]2([C:45]([OH:47])=[O:46])[CH2:30][CH2:29]1)[C@@:35]1([CH3:43])[C@@H:23]([C@:22]2([CH3:51])[C@@H:38]([CH2:37][CH2:36]1)[C@@:39]([CH2:41][OH:42])([CH3:40])[C@@H:19]([OH:18])[CH2:20][CH2:21]2)[CH2:24][CH2:25]3)=[CH2:49]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O[C@@H]6OC[C@H](O)[C@H](O)[C@H]6O[C@@H]6O[C@@H](C)[C@H](O)[C@@H](O)[C@H]6O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: CO
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 35 °C
Reaction time: 96 h
Yield: 85 %

Procedure:
To a solution of HCl methanol reagent 10 (10 mL) was added Pulchinenoside A (DA001, 100 mg) and the resulting mixture was stirred at 35° C. for 4 days. After pouring into water (10 ml), the mixture was extracted with chloroform (3×50 ml). The combined organic layer was washed with H2O (1×10 ml), brine (1×10 ml), dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel using CH2Cl2-MeOH (v/v, 30:1) to yield the desired product as a white solid with 85% yield.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:12]=[C:13]([C:18]4[S:22][C:21]([C:23]5([NH:27]S(C(C)(C)C)=O)[CH2:26][CH2:25][CH2:24]5)=[N:20][CH:19]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:27][C:23]1([C:21]2[S:22][C:18]([C:13]3[CH:12]=[C:11]([NH:10][C:6]4[N:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[CH:9]=[CH:8][N:7]=4)[CH:16]=[C:15]([CH3:17])[CH:14]=3)=[CH:19][N:20]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC3)s2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cnc(C3(N)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109 %

Procedure:
To a solution of the product of Step 2 (182 mg, 0.38 mmol) in dioxane (3.8 mL) was added hydrochloric acid 4.0 M in dioxane (0.95 mL, 3.78 mmol) and the mixture was stirred for at room temperature for 2 h. The mixture was concentrated under reduced pressure to provide 170 mg (0.41 mmol, 109%) of N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-cyclopropylpyrimidin-2-amine hydrochloride. MS ESI: [M+H]+ m/z 378.2. 1H NMR (600 MHz, d6-DMSO) δ 9.54 (s, 1H), 8.95 (s, 2H), 8.25 (d, J=4.8, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.40 (s, 1H), 7.11 (s, 1H), 6.83 (d, J=4.8, 1H), 2.66 (m, 2H), 2.57 (m, 2H), 2.28 (s, 3H), 2.14 (m, 1H), 2.03 (m, 2H), 1.10-1.04 (m, 4H). rhSYK activity=+++
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][C:8]3([CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:26]1[CH2:27][CH2:28][N:23]([C:2]2[CH:3]=[C:4]3[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][C:8]4([CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]3=[N:6][CH:7]=2)[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CC2(CCOCC2)c2ncc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure N using tert-butyl 6′-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]-1′(2′H)-carboxylate (12.0 g, 32.5 mmol), morpholine (3.11 mL, 35.7 mmol), Pd2dba3 (1.19 g, 1.30 mmol), XPhos (1.24 g, 0.08 mmol) and sodium tert-butoxide (6.25 g, 65.0 mmol) in toluene (200 mL) at 110° C. for 5 h. Purification by column chromatography (hexanes:EtOAC, 1:0 to 1:3 as eluent) gave tert-butyl 6′-morpholino-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]-1′(2′H)-carboxylate. Mass Spectrum (ESI) m/e=376.2 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Cl.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.O>CN(C=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([N:27]3[CH2:28][CH2:29][CH:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=4)[CH2:25][CH2:26]3)=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: O=C(O)Cc1ccc2nccnc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2nccnc2c1)N1CCC(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
0.48 g (2.55 mmol) of quinoxalin-6-ylacetic acid is mixed in 25 ml of DMF, and 1.07 ml of TEA, 0.68 g (2.55 mmol) of 4-(3-(trifluoromethyl)phenyl)piperidine hydrochloride and 1.13 mg of BOP are added thereto. The mixture is heated at ambient temperature overnight, 200 ml of water are added and extraction is carried out with ethyl acetate. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated under reduced pressure. A dark oil is thus obtained, which oil is purified by flash chromatography on a column of silica gel, elution being carried out with ethyl acetate. 0.76 g of the title product is obtained in the form of a yellow oil.
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]=[C:15]([CH2:18][C:19]([O:21]C)=[O:20])[CH:16]=[CH:17][C:3]1=2.[Br:23]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(Cl)(Cl)Cl>[Br:23][C:17]1[C:3]2[N:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5](=[O:13])[C:4]=2[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)O)cc(Br)c21
Yield: 10.9 %

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (0.750 g) was dissolved in chloroform (10 ml), and N-bromosuccinimide (0.550 g) was added to the solution. The mixture was refluxed overnight, and cooled. The mixture was then washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oily material. A 10% sodium carbonate aqueous solution (15 ml) and ethanol (10 ml) were added to the oily material, and the mixture was refluxed overnight. The contents were concentrated to 1/3 the original volume under reduced pressure with heating. The concentrate was treated with activated carbon powder, and acidified with 10% HCl with ice cooling. The precipitated crystals were collected by filtration and recrystallized from acetone to afford 5,6-dihydro-4-bromo-5-methyl-11-oxodibenz[b,e]azepine-2-acetic acid (prismatic crystals, 0.100 g) having a melting point of 164°-167° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1ccc(F)c2ccccc12
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: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2ccc(F)c3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 4-fluoro-naphthalene-1-carboxylic acid (232 mg, 1.22 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (250 mg, 1.22 mmol), HATU (696 mg, 1.83 mmol) in anhydrous DMF (8 mL) is added DIPEA (302 μL, 1.83 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (43) as white solid (340 mg, 74%).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[N:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=3)=[N:15]2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[I:25][C:21]1[CH:20]=[C:19]([C:16]2[N:17]=[N:18][N:14]([CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:26])=[O:5])=[CH:12][CH:11]=3)[N:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2nnc(-c3cccc(I)c3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2nnc(-c3cccc(I)c3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The ester (2.5 g, 5.41 mmol) prepared in Step (b) was suspended in dichloromethane (20 mL) followed by the addition of trifluoroacetic acid (5 mL). The solution was stirred for 16 hours at 25° C., then concentrated in vacuo. The resulting white solid was triturated with hexane/diethyl ether and the carboxylic acid (2.1 g, 100%) was collected by filtration. Mp 241–242° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:33]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1>C1COCC1.CCCCC>[CH:2](=[C:33]1[CH2:34][CH2:35][C:36](=[O:39])[CH2:37][CH2:38]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)CC1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C1CCC(=Cc2ccccc2)CC1
Reaction time: 5 h
Yield: 120 %

Procedure:
To a mechanically stirred suspension of 15.24 g (0.035 mole) of benzyltriphenylphosphonium bromide in 150 ml of THF there was added first 22 ml of 1.61 N n-butyllithium in pentane and then 5.0 g (0.032 mole) of cyclohexane-1,4-dione, ethylene monoketal in 50 ml of THF. Following 5 hours' heating at reflux the mixture was allowed to cool and was then washed in turn with water and brine. The organic layer was concentrated, and the residue was chromatographed on 1 liter of silica gel, eluting with 20% ethyl acetate in Skellysolve® B, to afford 7.15 g (97%) of 4-benzylidenecyclohexanone, ethylene ketal as an oil, the nmr spectrum of which is in consonance with the structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2].[CH2:34]([NH:36][CH3:37])[CH3:35]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:36]([CH2:34][CH3:35])[CH3:37])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2]
Reactant: CCNC
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c(N(C)CC)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A solution of 6-chloro-4-(2-chloro-benzyl)-8-fluoro-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (108 mg, 0.205 mmol, Eq: 1.00) and ethyl-methyl-amine (12.7 mg, 18.5 μl, 0.215 mmol, Eq: 1.05) in DMSO (1.5 ml) was heated to 40° C. for 65 h. Additional ethyl-methyl-amine (60.6 mg, 88.1 μl, 1.02 mmol, Eq: 5) was added and the solution was heated to 80° C. for 1.5 h. The solution was cooled to RT, diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×) and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 96.5:3.5) to afford the title compound as yellow solid (48 mg). MS (ESI): 435.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].CC1C=C(C)[N:12]([C:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[S:20])=N)N=1>CS(C)=O>[C:16]([N:18]1[C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[CH2:2][S:20]/[C:19]/1=[N:21]\[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:12]
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1cc(C)n(C(=N)NC(=S)NCCNC(=O)OC(C)(C)C)n1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC/N=C1\SCC(O)(C(F)(F)F)N1C#N
Temperature: 60 °C

Procedure:
A solution of 484 mg (2.4 mmol) of 3-bromo-1,1,1-trifluoropropan-2-one in 12 ml of DMSO is added dropwise to the crude mixture from Example 72A while cooling in ice, and the mixture is then heated at 60° C. for 1 h. The crude mixture is poured into ice-water and extracted three times with ethyl acetate. After the combined organic phases have been dried, the solvent is completely removed and the residue is purified by subsequent purification by preparative HPLC. 640 mg (67% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[C:23]([CH3:25])[C:22]([CH:26]=[O:27])=[CH:21][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2].[O-:28][Mn](=O)(=O)=O.[K+]>O1CCCC1.O>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:5]([C:4]3[C:3]([CH2:1][CH3:2])=[CH:24][C:23]([CH3:25])=[C:22]([CH:21]=3)[C:26]([OH:28])=[O:27])=[O:6])[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: CCc1cc(C)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a round-bottom flask was added a solution of 4-(1-(2-ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 211.5, 720 mg, 2.00 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). A solution of KMnO4 (640 mg, 4.05 mmol, 2.00 equiv) in water (20 mL) was added dropwise. The resulting solution was stirred for 15 h at 60° C. then cooled to rt with a water bath. The solids were removed with filtration. The filtrate was extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 600 mg (80%) of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acid as a light yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].C1CCN2C(=NCCC2)CC1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([S:29][CH3:30])[N:23]=1.Cl>CN(C=O)C>[Cl:21][C:22]1[CH:27]=[C:26]([NH:9][NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[N:25]=[C:24]([S:29][CH3:30])[N:23]=1
Reactant: NNC(=O)c1ccco1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(Cl)cc(NNC(=O)c2ccco2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Into 150 mL of DMF, 65 g (515 mmol) of 2-furoic hydrazide and 70 mL (510 mmol) of DBU were dissolved, and a DMF solution of 4,6-dichloro-2-methylthiopyrimidine (50.0 g (256 mmol)/100 mL) was slowly added dropwise thereto at room temperature (inner temperature was controlled at 45° C. or lower). After stirring at room temperature for about 2 hours, the reaction solution was poured into ice-water and the pH was adjusted to 6 to 7 with a 2 mol/L hydrochloric acid solution, followed by collecting the resulting solid through filtration. The collected solid was dissolved into an organic solvent (chloroform/methanol=10/1) and, after washing with water, the solution was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was triturated twice with chloroform to obtain 56.9 g of Compound A as white flocculent crystals (yield: 78%). The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=6/4) to additionally recover Compound A in about 10% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:35])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]4)=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1)=O.[BH4-].[Li+].CO>C1COCC1>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:7]4[CH:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][C:8]=4[CH3:11])=[CH:17][CH:16]=3)=[O:35])=[CH:21][CH:22]=2)[CH2:28][CH2:29]1
Reactant: COC(=O)c1ccc(C)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CO)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
4′-[4-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-carboxylic acid methyl ester (565 mg) in dry THF (6 ml) was treated with a solution of lithium borohydride (2M in THF, 3.5 ml). The mixture was stirred at 20 C for 18 h. and was then treated with methanol (5 ml). The mixture was then evaporated and the residue partitioned between water and ethyl acetate. The dried extracts were evaporated giving the title compound as a colourless crystalline solid (505 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:44][CH2:45][Cl:46]>CC#N.O>[Cl:46][CH2:45][CH2:44][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24]
Reactant: ClCCBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCCCN(CCCC)C(=O)c1cn(CCCl)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
To a solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (275 mg, 0.56 mmol) in dry MeCN (8.0 mL) was added cesium carbonate (182 mg, 0.56 mmol) and 1-bromo-2-chloroethane (80 mg, 0.56 mmol). The reaction mixture was heated at 50° C. for 10 h, diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (gradient from 0% to 2% MeOH/CH2Cl2) to provide the title compound (170 mg, 54%). 1H NMR (DMSO-d6) δ 8.46 (d, J=1.6 Hz, 1H), 8.26 (dd, J=8.0, 1.6 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.36-7.33 (m, 3H), 7.27-7.25 (m, 2H), 5.16 (s, 2H), 4.08-4.03 (m, 4H), 3.93 (s, 1.5H), 3.77-3.73 (m, 3.5H), 3.50-3.40 (m, 2H), 1.50-1.45 (m, 4H), 1.35-1.10 (m, 4H), 0.92-0.75 (m, 6H); MS(ESI+) m/z 555.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([NH:15][CH2:14][CH2:13][O:12][CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: COCCN
Reactant: N#Cc1cnc(N)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COCCNc1cc(N)ncc1C#N
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.10 g, 8.02 mmol) in DMA (20 ml) was treated with 2-methoxyethylamine (2.07 ml, 24.1 mmol) and DIPEA (4.20 mL, 24.1 mmol), heated to 50° C. and stirred for 15 h. The reaction mixture was cooled to room temperature and concentrated. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated and dried under vacuum to give the title compound as an off-white solid.
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.[CH3:65][O:66][C:67]1[N:72]=[C:71]2[C:73]([CH2:76][C:77](O)=[O:78])=[CH:74][NH:75][C:70]2=[CH:69][CH:68]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:77](=[O:78])[CH2:76][C:73]2[C:71]3=[N:72][C:67]([O:66][CH3:65])=[CH:68][CH:69]=[C:70]3[NH:75][CH:74]=2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2n1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: COc1ccc2[nH]cc(CC(=O)NC(Cc3cc(F)cc(F)c3)c3ncoc3-c3ccc(Cl)cc3)c2n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.65 (d, J=8.6 Hz, 1H), 8.46 (s, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.27 (s, 1H), 6.89 (t, J=9.6 Hz, 1H), 6.74 (d, J=6.8 Hz, 2H), 6.60 (d, J=8.6 Hz, 1H), 5.35 (q, J=7.8 Hz, 1H), 3.87 (s, 3H), 3.50 (s, 2H), 3.17-2.98 (m, 2H). MS (m/z) 523.1 [M+H]+.