Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OC)c2)n(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.50 g (4.20 mmol) of the compound of Example 31A are provided in 20 ml of 1,4-dioxane, 20 ml (20 mmol) of a 1N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 1 h. The mixture is concentrated, a 1N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with ethyl acetate, and the combined organic phases are dried over magnesium sulfate, filtered and concentrated. 1.32 g (92% of theory) of the title compound are obtained.
Reaction SMILES: C1(/C=[CH:8]/[C:9]2[NH:18][C:17]3[C:12]([O:13][CH2:14][C:15](=[O:19])[N:16]=3)=[CH:11][N:10]=2)C=CC=CC=1.[O:20]1CCOCC1>O.C(Cl)Cl.O=[Os](=O)(=O)=O>[O:19]=[C:15]1[CH2:14][O:13][C:12]2=[CH:11][N:10]=[C:9]([CH:8]=[O:20])[NH:18][C:17]2=[N:16]1
Reactant: C1COCCO1
Reactant: O=C1COC2=CN=C(/C=C/c3ccccc3)NC2=N1
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Solvent: O
Product: O=CC1=NC=C2OCC(=O)N=C2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-[(E)-2-phenylethenyl]-1H-pyrimido[5,4-b][1,4]oxazin-7(6H)-one (106 mg, 0.418 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added NaIO4 (357 mg, 1.67 mmol) and OsO4 (00.1 mL, 4% wt in water) and the reaction mixture was stirred at room temperature. After 2 h, and additional 3 mL of 1,4-dioxane and 180 mg of NaIO4 were added. After a total of 7.5 h, the reaction was capped and stored in a freezer for the weekend. After warming to room temperature, additional OsO4 (0.1 mL, 4% wt in water) was added and the reaction was stirred for an additional 4 h. The solvent was evaporated to give a white solid which was dissolved in DCM and water. The aqueous layer was extracted with 10% MeOH-DCM (6×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give a light tan solid (92 mg) which was not purified further.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[OH:16][CH:15]([C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CSc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
380 mg of 1-bromo-4-methylsulfanyl benzene was dissolved in 10 mL anhydrous tetrahydrofuran, and 1.24 mL solution of 1.59 M n-butyl lithium in hexane was added dropwise thereto at −70° C. After the mixture was stirred for 1 hour, 3 mL solution of 400 mg t-butyl 4-formyl-piperidine-1-carboxylate in anhydrous tetrahydrofuran was added dropwise thereto, and the mixture was stirred at −70° C. for 2 hours. The temperature of the reaction mixture was increased gradually to 0° C., then water and an ammonium chloride solution were added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and purified by silica gel column chromatography (ethyl acetate/hexane) to give 150 mg of the title compound as a colorless amorphous.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[OH2:14]>>[O:14]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8]1
Reactant: O
Reactant: CC(=O)NC1CCCc2sccc21
Product: CC(=O)NC1CCC(=O)c2sccc21
Temperature: 60 °C

Procedure:
Into a 100 ml, three necked round bottomed flask is placed 2.0 g of N-(4,5,6,7-tetrahydrobenz[b]-thien-4-yl)acetamide, 15 ml of H2O, and 31.5 ml of a 1.3 M cobaltic acetate solution prepared as in Example II. The mixture is stirred and heated to 60° C. under N2 for 12 hours and is worked up as in Example V. A material weighing 1.9 g and assaying as 76.8% of the product was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][N:7]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:15]=[CH:16][C:17]=2[N+:18]([O-])=O)=[O:10])[CH2:6]1)[CH3:3]>CO.[Pd]>[NH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:13][C:12]=1[NH:11][C:9]([N:7]1[CH2:6][CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:8]1)=[O:10]
Reactant: CN(C)CC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2N)C1
Reaction time: 2 h
Yield: 2.2 %

Procedure:
To a solution of 3-((dimethylamino)methyl)-N-(4′-fluoro-4-nitro-[1,1′-biphenyl]-3-yl)azetidine-1-carboxamide (1.7 g, 4.57 mmol, 1.0 eq.) in methanol (100 mL) and was added 10% Pd/C (1.0 g, 0.94 mmol). The reaction mixture was stirred 2 h under a hydrogen atmosphere. The reaction was then filtered and the filtrate was concentrated under reduced pressure to give N-(4-amino-4′-fluoro-[1,1′-biphenyl]-3-yl)-3-((dimethylamino)methyl)azetidine-1-carboxamide (35 mg, 3% yield) as an off-white solid. ESI+ MS: m/z 343 ([M+H]+), 1H NMR (500 MHz, DMSO-d6): δ 7.61 (s, 1H), 7.53-7.51 (m, 2H), 7.36 (d, J=2.0 Hz, 1H), 7.21-7.15 (m, 3H), 6.76 (d, J=8.5 Hz, 1H), 4.98 (s, 2H), 3.99 (t, J=8.0 Hz, 2H), 3.58 (dd, J1,2=6.0 Hz, J1,3=8.0 Hz, 2H), 2.72-2.69 (m, 1H), 2.45-2.44 (m, 2H), 2.13 (s, 6H).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:27])[CH:7]([CH:8]=C(C)C)[CH:6]1[C:12]([O:14][CH2:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])=[O:13]>C(OCC)(=O)C>[CH3:4][C:5]1([CH3:27])[CH:7]([CH:8]=[O:1])[CH:6]1[C:12]([O:14][CH2:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])=[O:13]
Reactant: O=[O+][O-]
Reactant: CC(C)=CC1C(C(=O)OCc2c(F)c(F)c(F)c(F)c2F)C1(C)C
Solvent: CCOC(C)=O
Product: CC1(C)C(C=O)C1C(=O)OCc1c(F)c(F)c(F)c(F)c1F
Yield: 89 %

Procedure:
Ozone gas was bubbled at -78° C. into a solution of 3.48 g (10.0 mmol) of pentafluorophenylmethyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate obtained in Reference Example 4, in 20 ml of ethyl acetate. The subsequent operation was conducted in the same manner as in Reference Example 5, whereby 2.87 g of pentafluorophenylmethyl 2,2-dimethyl-3-formylcyclopropanecarboxylate was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[Br:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([O:18][CH3:17])=[O:28])=[C:21]([Br:27])[CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: COC(=O)c1ccc(N)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (355 mg, 1.52 mmol), and 4-amino-2-bromo-benzoic acid methyl ester (prepared as described in Part C) (350 mg, 1.52 mmol), HBTU (865 mg, 2.282 mmol) and DIPEA (0.531 mL, 3.04 mmol) in CH2Cl2 (15 mL) was stirred at RT for 60 h. Additional aliquots of (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (180 mg), HBTU (580 mg) and DIPEA (0.265 mL) were added to the mixture, and stirring was continued at RT for 20 h and subsequently at 40° C. for 24 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with water, 1N aqueous HCl (3×), aqueous NaHCO3 solution (2×) and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane gradient 1:3 to 1:2) to afford the title compound as a white foam. TLC Rf (EtOAc/c-hexane 1:2)=0.24; MS (LC/MS): 468 [M+Na]+, 388/390 [MH−tBu]+, 345/347 [MH−Boc]+; tR (HPLC conditions b): 4.36 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Cl)ccc1N

Procedure:
A solution of 6-chloro-3-nitropicolinamide (0.30 g, 1.49 mmol) in EtOAc (30 mL) is hydrogenated at 60 psi over 5% Pd-C (0.10 g) for 20 min. After removal of the catalyst by filtration the solution is concentrated to dryness to give 3-amino-6-chloropicolinamide as a yellow oil, which is used directly in the next step. It is dissolved in triethylorthoformate (30 mL) and the mixture is heated under reflux for 18 h. Petroleum ether (30 mL) is added to the cooled solution, and the resulting precipitate of crude 6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (0.27 g, 99%) is filtered off and dried in a vacuum oven.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][NH:5][CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9][CH3:10])=[O:8].[C:35]([O-])(O)=O.[Na+].CI>CO>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][N:5]([CH3:35])[CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])O
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NCc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)N(C)Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To 100 mg of (methyl 2-[(2,6-dichlorobenzyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate) 41 in CH3OH (2.3 ml) are added, at 0° C., NaHCO3 (1 equ.) and CH3I (1 equ.). The reaction is stirred for 1 h at 0° C., and then at room temperature for 2 days. The solvent is evaporated and CH2Cl2 (10 ml) is added to the residue. The solution is washed with water, brine, again water and dried over MgSO4, filtered and evaporated. Due to an incomplete reaction, the protocol is repeated using a tenfold excess of NaHCO3 and CH3I in MeOH (5 ml). After a similar work-up, the residue is purified by silica gel chromatography using hexane/AcOEt 90/10 as eluent to give methyl 2-[(2,6-dichlorobenzyl)(methyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 51.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3](=[O:23])[CH2:4][O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[N:15][C:16]3[NH:17][CH2:18][CH2:19][CH2:20][C:21]=3[CH:22]=2)[CH:12]=1.FC(F)(F)[C:27]([OH:29])=[O:28]>C(Cl)Cl>[C:7]([O:29][C:27]([N:17]1[C:16]2[C:21](=[CH:22][C:13]([C:11]3[CH:10]=[N:9][CH:8]=[C:7]([CH2:6][O:5][CH2:4][C:3](=[O:23])[N:2]([CH3:24])[CH3:1])[CH:12]=3)=[CH:14][N:15]=2)[CH2:20][CH2:19][CH2:18]1)=[O:28])([CH3:8])([CH3:12])[CH3:6]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)C(=O)COCc1cncc(-c2cnc3c(c2)CCCN3)c1
Solvent: ClCCl
Product: CN(C)C(=O)COCc1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1

Procedure:
6-(5-Dimethylcarbamoylmethoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is synthesized according to the procedure of Suzuki Coupling Method III, as illustrated above. It is then used to prepare N,N-dimethyl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethoxy]-acetamide according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent.
Reaction SMILES: Cl.Cl.NC1CCN(C2CCCCC2(CCC2C=C(C3C=CC([Cl:31])=C(Cl)C=3)C=CC=2)O)CC1.[Cl:33][C:34]1[CH:35]=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]([C:63]3([OH:69])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]3)[CH2:48][N:49]3[CH2:54][CH2:53][CH:52]([NH:55]C(=O)OC(C)(C)C)[CH2:51][CH2:50]3)[CH:42]=2)[CH:37]=[CH:38][C:39]=1[Cl:40].Cl>>[ClH:31].[ClH:33].[NH2:55][CH:52]1[CH2:53][CH2:54][N:49]([CH2:48][CH:47]([C:63]2([OH:69])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]2)[C:43]2[CH:42]=[C:41]([C:36]3[CH:37]=[CH:38][C:39]([Cl:40])=[C:34]([Cl:33])[CH:35]=3)[CH:46]=[CH:45][CH:44]=2)[CH2:50][CH2:51]1
Reactant: NC1CCN(C2CCCCC2(O)CCc2cccc(-c3ccc(Cl)c(Cl)c3)c2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: NC1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 135, step 3 1-[2-(4-aminopiperidin-1-yl)-1-(3′,4′-dichloro-1,1′-biphenyl-3-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {1-[2-(3′,4′-dichloro-1,1′-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate. MS (ES) m/z 447.2 ([M+H]+); HRMS: calcd for C25H32Cl2N2O.2.00 HCl, 518.1425; found (ESI), 447.1962.
Reaction SMILES: [C-:1]1([C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9]([O:11]CC)=[O:10])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28].[OH-].[K+]>C(O)C>[C-:1]1([C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9]([OH:11])=[O:10])=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5]1.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]
Reactant: CCCCCCCCCC(C(=O)OCC)C(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCC(C(=O)O)C(=O)[c-]1cccc1
Yield: 97.5 %

Procedure:
An amount of 12.4 g of ethyl ferrocenoylundecanate prepared in (1) above and 2.9 g of potassium hydroxide were refluxed for 2 hours in an ethanol solvent and then was subjected to acid treatment to obtain 11.3 g of ferrocenoylundecanic acid represented by the following formula: ##STR27##
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:30][O:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][NH2:35]>>[CH3:30][O:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][NH:35][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:16]
Reactant: COCC(C)(C)CN
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Agent: Cl
Product: COCC(C)(C)CNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 54 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 3-methoxy-2,2-dimethylpropan-1-amine hydrochloride, the title compound as yellow solid (54%).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O.[Cu]>[Cl:8][C:7]1[C:2]([C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ncc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 56 g (0.246 mol) of 2-bromo-3,5-dichloropyridine in 500 mL of dry dimethylsulfoxide, were added 53 g (0.261 mol) of ethyl bromodifluoroacetate followed by 94 g (0.518 mol) of copper bronze (200 mesh). The beige suspension was heated at 50° C. for 5 hours. After cooling of the reaction mixture, a solution of 44 g (0.328 mol) of potassium monophosphate in 280 mL of water was added and stirred for 1 hour. The black mixture was then filtered over a cake of Supercel™, and the cake was washed three times by 200 mL of ethyl acetate. The organic phases were collected, washed with brine and dried over magnesium sulfate. Evaporation of the solvent under vacuum gave 57.6 g of brown oil. After purification by column chromatography on silica gel (heptane/ethyl acetate 9/1) 40 g (57%) of ethyl (3,5-dichloropyridin-2-yl)(difluoro)acetate (Int-7) were obtained as a yellow oil, (M+1)=270, 19F-NMR (235 MHz, CDCl3) δ (ppm): −104.21 (CF2).
Reaction SMILES: [CH2:1]([CH:8]1[S:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH:21]=[C:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[Pd]>[CH2:1]([CH:8]1[S:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCN3C(=O)SC(Cc4ccccc4)C3=O)cc2)S1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCN3C(=O)SC(Cc4ccccc4)C3=O)cc2)S1

Procedure:
5-(4-[2-(5-Benzyl-2, 4-thiazolidinedion-3-yl ) -ethoxy]benzylidene)-2,4-thiazolidinedione (3.0 g) was dissolved in dioxan (400ml) and hydrogenated over 10% Palladium-charcoal (6 g) at 150 psi overnight. The reaction mixture was filtered through diatomaceous earth, the filter-cake washed with dioxan, and the combined dioxan solutions evaporated to afford the title compound as a gum. This material was used directly in salt formation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([C:30]#[N:31])=[C:20]([OH:32])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.C(O)(=[O:40])C>C(O)C.O>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]([C:30](=[O:40])[NH2:31])=[C:20]([OH:32])[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(C#N)cc3-c3ccccc3)cc2)CCC1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(C(N)=O)cc3-c3ccccc3)cc2)CCC1
Temperature: 50 °C
Yield: 72 %

Procedure:
To a suspension of tert-butyl(1-(4-(5-cyano-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (14.6 g, 3.58 g, 0.033 mol) in ethanol (112 ml) and water (112 ml) at room temperature was added sodium hydroxide solution (6M, 54.4 ml) and hydrogenperoxide (30%, 21.9 ml). The resulting mixture was heated at 50° C. for 16 h. After cooled down to 0° C., the mixture was added acetic acid to adjust pH=4. The resulting precipitate was filtered and the filter cake was dried to give the title compound as white solid (10.8 g, 72%). LCMS (Method A): RT=5.88 min, M+1=460. 1H NMR (500 MHz, DMSO-d6): 9.65 (1H, br), 8.10 (1H, s), 7.25-7.05 (7H, m), 6.98 (2H, m), 2.45-2.25 (4H, m), 2.0-1.95 (1H, m), 1.79-1.75 (1H, m), 1.3-1.0 (91-1, br).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24]([O:30][CH3:31])=[N:25][CH:26]=[C:27]([Cl:29])[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[Cl:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]3[CH3:21])=[CH:4][CH:3]=2)[C:24]([O:30][CH3:31])=[N:25][CH:26]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Reactant: COc1ncc(Cl)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ncc(Cl)cc1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cn1
Temperature: 100 °C
Yield: 56 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (40 mL), (S)-tert-butyl 4-(6-amino pyridin-3-yl)-3-methylpiperazine-1-carboxylate 101h (2.04 g, 7.0 mmol), 3-bromo-5-chloro-2-methoxypyridine (2.8 g, 12.6 mmol), Pd2(dba)3 (640 mg, 0.70 mmol), XantPhos (404.6 mg, 0.70 mmol), and cesium carbonate (4.56 g, 14.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 4 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:3 ethyl acetate/petroleum ether to afford 271a (1.7 g, 57%) as a yellow solid. MS-ESI: [M+H]+ 434.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[O:20][CH3:21])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: COc1cccc(OC)c1
Product: COc1ccc(Cc2cc(Br)ccc2Cl)c(OC)c1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and 1,3-dimethoxybenzene.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([N:9]3[CH2:10][CH2:11][C@H:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)[CH:13]=2)[CH2:18]1
Reactant: Brc1nc2ccccc2o1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2nc4ccccc4o2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-benzooxazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2Br)=[O:8])[CH3:2].[CH3:24][Sn](C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2[CH3:24])=[O:8])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Br)c2sc1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(C)c2sc1=O
Temperature: 120 °C
Yield: 94.5 %

Procedure:
[(8-Bromo-6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (500 mg, 1.19 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL). Tetramethyl tin (247 μL, 1.783 mmol), dichloro(bis-triphenylphosphino) palladium (125 mg, 0.18 mmol), and 4 angstrom molecular sieves were added sequentially to the reaction. The reaction was sealed and heated to 120° C. in an oil bath for 45 min. The reaction was cooled, diluted with ethyl acetate, and partitioned with water. The organic phase was washed with water, brine, and dried over sodium sulfate. The crude material was purified by silica gel chromatography (15%-45% ethyl acetate in hexanes) to provide [(6-chloro-4-hydroxy-8-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (400 mg, 95%). MS ESI(−) m/e: 354.223 (M−1).