Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][S:21][CH2:22][C:23](OCC)=[O:24])[CH:6]=[CH:7][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][S:21][CH2:22][CH2:23][OH:24])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CSCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCSCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
Under an argon atmosphere, 200 mg (0.446 mmol) of ethyl 2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methylthio)-acetate were dissolved in 4 ml of tetrahydrofurane and 33.9 mg (0.892 mmol) of LiAlH4 were added. The solution was heated to 50° C. for 1 h. 0.030 ml of water were slowly added, followed by the addition of 0.030 ml of 6N sodium hydroxide and then with 0.1 ml of water. After 30 min of stirring, the precipitate was filtered, and washed with ethyl acetate. The collected organic phases were washed with brine and then dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The obtained solid was triturated in ethyl acetate, filtered and then washed with ethyl acetate. 50 mg (yield=28%) of 2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)-methylthio) ethanol were obtained as a white solid. LC-MS: m/z=407 (MH+) UV purity at 254 nm=89%. 1H NMR (300 MHz, DMSO) δ 8.30 (d, 1H), 8.12 (s, 1H), 7.99 (m, 1H), 7.75 (m, 2H), 7.03 (m, 1H), 6.88 (d, 1H), 4.84 (t, 1H), 3.96 (s, 5H), 3.60 (m, 2H), 2.67 (t, 2H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28](N)=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].BrCCO[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:27][CH2:28][O:29][CH:35]6[CH2:40][CH2:39][CH2:38][CH2:37][O:36]6)[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Reactant: BrCCOC1CCCCO1
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCOC4CCCCO4)C3)ccc1-2

Procedure:
The title compound was prepared by a similar method to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using 2-(2-bromoethoxy)tetrahydro-2H-pyran instead of 2-bromoacetamide and DMF instead of THF and performing the reaction at 60° C. The title compound was isolated as an amber gum (104 mg, 29%). LCMS: RT=3.24, 3.35 min, [M+H]+=496
Reaction SMILES: [CH2:1]([C:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:1]([C:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2cccs2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1
Product: C=CCC1(c2cccs2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1

Procedure:
The two diastereomers of the title compound were prepared separately from the diastereomers of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 111 using 4-fluorophenylboronic acid. The diastereomers were separated.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH:21]([S:30][CH2:31][CH2:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[S:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1>CO.[OH-].[Li+].O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH:21]([S:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[S:30][CH2:31][CH2:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCCSC(SCCC(=O)N(C)C)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)CCSC(SCCCC(=O)O)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
To a solution of 7-chloro-2-[5-{[2-(dimethylcarbamoyl)ethylthio](3-methoxycarbonylpropylthio)methyl}-benzofuran-2-yl]quinoline (0.49 g) in methanol (5 ml), 1N aqueous lithium hydroxide (1.32 ml) was added at ambient temperature under nitrogen atmosphere. After being stirred for 15 hours at ambient temperature, the resulting mixture was concentrated under reduced pressure to give a syrup. The syrup was dissolved in water, washed with diethyl ether, adjusted to pH 4 with diluted aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol. The fractions containing object compound were combined and concentrated in reduced pressure to give a syrup of 7-chloro-2-[5-{(3-carboxypropylthio)[2-(dimethylcarbamoyl)ethylthio]methyl}benzofuran-2-yl]quinoline (0.35 g).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1.I[CH3:18]>O1CCCC1>[S:3]1[C:7]2[CH:8]=[C:9]([N:12]([CH3:18])[S:13]([CH3:16])(=[O:14])=[O:15])[CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: CS(=O)(=O)Nc1ccc2ncsc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc2ncsc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
Sodium hydride (2.56 g of a 60% dispersion in mineral oil, 64.0 mmol) was added to a solution of N-benzothiazol-6-yl-methanesulfonamide (Example 7a, 13.3 g, 58.2 mmol) in tetrahydrofuran at 0° C. After 15 min, iodomethane (36.2 mL, 581 mmol) was added and the reaction mixture was warmed to 25° C., stirred for 4 h, then was partitioned between 1.0 M aqueous hydrochloric acid solution (300 mL) and ethyl acetate (2×250 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether afforded a solid that was collected by vacuum filtration and dried in vacuo to afford the desired product, N-benzothiazol-6-yl-N-methyl-methanesulfonamide (12.1 g, 50 mmol, 86% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.00 (3H, s), 3.31 (3H, s), 7.57 (1H, dd, J1=2.2 Hz, J2=8.7 Hz), 8.07 (1H, d, J=8.5 Hz), 8.23 (1H, d, J=1.7 Hz), 9.40 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O.B>C1COCC1>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: B
Solvent: C1CCOC1
Product: CN(C)CCN1CCCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
A solution of 1-(2-(dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1.0 g, 3.80 mmol) in 10 mL THF was cooled to 0° C. and treated with a solution of 1M borane in THF (21.5 mL, 21.50 mmol). The solution was heated at reflux for 6 hours then stirred at room temperature for 1 day. After this time, the mixture was cooled to 0° C. and quenched with methanol (5 mL). The mixture was concentrated, dissolved in methanol (20 mL), stirred at room temperature for 3 days then heated at reflux for 6 hours. The reaction was concentrated and the residue was subjected to Biotage silica gel chromatography using a gradient of 1-10% 2M NH3 in MeOH/CH2Cl2 to give a viscous oil (598 mg, 63.1%). 1H-NMR (CDCl3) δ 7.96 (dd, J=2.7, 9 Hz, 1H), 7.85 (d, J=2.1 Hz, 1H), 6.48 (d, J=9 Hz, 1H), 3.50-3.43 (m, 4H), 2.78 (t, J=6.3 Hz, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.29 (t, 6H), 1.99-1.94 (m, 2H). MS (ESI): 250.2 (M+1).
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[O:3][C:2]=1[CH2:8][OH:9].[O:10]=O>>[CH:8]([C:2]1[O:3][C:4]([C:6]([OH:10])=[O:7])=[CH:5][CH:1]=1)=[O:9]
Reactant: O=Cc1ccc(CO)o1
Reactant: O=O
Product: O=Cc1ccc(C(=O)O)o1

Procedure:
5-HMF feed is oxidized with elemental O2 in a multi-step reaction to form FDCA with 5-formyl furan-2-carboxylic acid (FFCA) as a key intermediate eq 1. Oxidation of 5-(acetoxymethyl)furfural (5-AMF), which contains an oxidizable ester and aldehydes moieties, produces FDCA, FFCA, and acetic acid, eq 2. Similarly oxidation of 5-(ethoxymethyl)furfural (5-EMF) produces FDCA, FFCA, 5-(ethoxycarbonyl)furan-2-carboxylic acid (EFCA) and acetic acid, eq 3.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][CH2:9][C:10]1[C:11]([F:18])=[C:12]([C:14]([F:17])=[CH:15][CH:16]=1)[NH2:13]>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:13][C:12]1[C:11]([F:18])=[C:10]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:9][NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: NCc1ccc(F)c(N)c1F
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (400 μL, 2.86 mmol) followed by pivaloyl chloride (60 μL, 0.52 mmol) are added to 3-aminomethyl-2,6-difluoro-aniline (120 mg as HCl salt) in THF (10 mL) and stirred at rt overnight. The reaction mixture is diluted with EtOAc and sat. NaHCO3-solution, the organic layer is washed with water and brine, dried and concentrated to give the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:14][C:15]4[N:20]([CH2:21][CH2:22][C:23]#N)[C:19](=[O:25])[CH2:18][O:17][C:16]=4[N:26]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.C(OC(=O)NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC)C(=O)COC=4N=3)=CC=2)CCC1)(C)(C)C>>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:14][C:15]4[N:20]([CH2:21][CH2:22][CH3:23])[C:19](=[O:25])[CH2:18][O:17][C:16]=4[N:26]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Agent: CCCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Product: CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(2-oxo-7-phenyl-1-propyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (40 mg, 0.078 mmol) was reacted to afford the title compound (16.5 mg). 1H NMR (500 MHz, CH3OD) 7.55 (1H, s), 7.41 (2H, d), 7.38 (2H, d), 7.32 (3H, m), 7.24 (2H, m), 4.96 (2H, s), 4.02 (2H, t), 2.73-2.78 (2H, m), 2.54-2.60 (2H, m), 2.20-2.28 (1H, m), 1.91-1.99 (1H, m), 1.71-1.79 (2H, m), 1.01 (3H, t). LCMS (Method D): RT=0.79 min, M+H+=414.2.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)=[O:4].Cl[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C(OCC)C>[F:19][C:16]([F:17])([F:18])[C:11]1[C:12]([C:14]#[N:15])=[CH:13][C:7]2[N:6]=[C:5]([C:3]3([C:2]([F:20])([F:1])[F:21])[O:25][CH2:24][CH2:23][O:4]3)[NH:9][C:8]=2[CH:10]=1
Reactant: OCCCl
Reactant: N#Cc1cc2nc(C(=O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N#Cc1cc2nc(C3(C(F)(F)F)OCCO3)[nH]c2cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile (0.50 g; 1.5 mmol), was dissolved in DMF (4 mL), then treated with 2-chloroethanol (0.35 mL; 5.2 mmol) and potassium carbonate (0.73 g; 5.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate (40 mL) and diethyl ether (40 mL), washed with water (50 mL) and brine (3×30 mL), then dried over Na2SO4. The reaction mixture was filtered, concentrated to yield a light brown solid, which was purified by column chromatography (SiO2; 100% ethyl acetate) to yield the title compound as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22]SC)[CH:5]=1)([O-:3])=[O:2].C[I:26]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][I:26])[CH:5]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: CSCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1CI

Procedure:
The mixture of 1.5 g of N-(4-nitro-2-methylmercaptomethylphenyl)-4-chlorophthalimide and 50 ml of methyl iodide is refluxed for 6 days in the absence of light and evaporated. The residue is taken up in hot benzene, the mixture filtered and evaporated to yield the N-(4-nitro-2-iodomethylphenyl)-4-chlorophthalimide melting at 183°-187°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]4[O:22][CH2:23][O:24][C:19]4=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N+]([O-])=O.C[O-].[Na+].[C:28](O)(=[O:30])C>CO>[CH3:28][O:30][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]4[O:22][CH2:23][O:24][C:19]4=[CH:18][C:16]=3[N:17]=2)[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)OCO3
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
A solution of 500 mg of 6-[[(3-methyl-4-nitro-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole in 20 ml of absolute methanol was treated with 300 mg of sodium methylate, whereupon the mixture was boiled at reflux under argon for 18 hours. The reaction mixture was buffered by means of glacial acetic acid and concentrated in vacuo. The residue was treated with methylene chloride/sodium bicarbonate solution, whereupon the organic solution was dried and concentrated. By recrystallization from ethyl acetate there was obtained 6-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 215°-220°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]1[NH:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH:49]([N:52]2[CH2:57][CH2:56][N:55]([C:58](=[O:72])[NH:59][C:60]3[CH:65]=[CH:64][C:63](Br)=[C:62]([O:67][C:68]([F:71])([F:70])[F:69])[CH:61]=3)[CH2:54][CH2:53]2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C(=O)(O)[O-].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.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].C(#N)C>[C:39]([O:43][C:44]([N:46]1[CH2:47][CH2:48][CH:49]([N:52]2[CH2:57][CH2:56][N:55]([C:58](=[O:72])[NH:59][C:60]3[CH:65]=[CH:64][C:63]([C:26]4[CH:25]=[CH:24][C:23]([C:21]5[N:22]=[C:18]([C@@H:12]6[CH2:13][C@H:14]([O:16][CH3:17])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[NH:19][CH:20]=5)=[CH:28][CH:27]=4)=[C:62]([O:67][C:68]([F:70])([F:71])[F:69])[CH:61]=3)[CH2:54][CH2:53]2)[CH2:50][CH2:51]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)Nc3ccc(Br)c(OC(F)(F)F)c3)CC2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)N4CCN(C5CCN(C(=O)OC(C)(C)C)CC5)CC4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A solution of [(S)-1-((2S,4S)-4-methoxy-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (35.5 mg, 0.067 mmol; Preparation 26), 4-[4-(4-bromo-3-trifluoromethoxy-phenylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (37.1 mg, 0.067 mmol) and sodium bicarbonate (29.4 mg, 0.35 mmol) in 1,4-dioxane (2.8 mL) and water (129 μL) was degassed with nitrogen for 20 min. Pd2(dba)3 (12.33 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (32.09 mg, 0.067 mmol) were added and the reaction was degassed with nitrogen for 15 min. The resulting solution was heated at 90° C. for 60 h, concentrated, diluted with methanol, filtered through a pad of Celite®, concentrated under vacuum, and purified by reverse phase HPLC. Fractions containing product were combined and lyophilised overnight to afford a white powder. Impure fractions were combined and concentrated under vacuum, dissolved in 1:1 acetic acid:ACN solution to provide the di-TFA salt of the title compound (40 mg, 54% yield) (m/z): [M+H]+ calcd for C43H57F3N8O8 871.43 found 871.8.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[CH2:16][CH2:15][C:14]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:13][CH2:12]2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN.O[N:47]1[C:51]2C=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH:1]1([CH:7]([N:11]2[CH2:12][CH2:13][C:14]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)([CH2:17][CH2:18][N:19]3[C@H:20]4[CH2:26][CH2:25][C@@H:24]3[CH2:23][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:21]4)[CH2:15][CH2:16]2)[C:8]([NH:47][CH3:51])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)O)C2CCCCC2)CC1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CNC(=O)C(C1CCCCC1)N1CCC(CCN2[C@@H]3CC[C@H]2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Reaction time: 24 h
Yield: 36.5 %

Procedure:
To a solution of cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (22.0 mg, 0.037 mmol), methylamine (0.056 mL of a 2M solution in THF, 0.11 mmol), N-hydroxybenzotriazole (10.1 mg, 0.075 mmol) and N-methylmorpholine (0.10 mL, 0.094 mmol) in 1 mL DMF was added EDC (14 mg, 0.075 mmol). The reaction mixture was stirred for 24 h, then diluted with 4:1 EtOAc:hex and washed with saturated aqueous NaHCO3, dried (Na2SO4) and chromatographed (5% (2M NH3/MeOH) in CHCl3) to provide 2-cyclohexyl-2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-N-methylacetamide (8.1 mg, 36%) as a solid. 1H NMR (400 MHz, CDCl3), δ 7.66 (m, 1H), 7.33-7.27 (m, 2H), 7.20-7.11 (m, 2H), 7.05 (m, 1H), 6.98 (m, 1H), 6.90 (m, 1H), 4.64 (m, 1H), 3.33-3.20 (m, 2H), 2.80 (d, 3H, J=4.9 Hz), 2.59 (s, 3H), 2.47-0.79 (m, 27H); ESI-MS 600 (M+H).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6][CH2:5]1)=[C:2]=[S:3].[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC1C=CC=CC=1>[N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:6][CH2:5]1)=[C:2]=[S:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: S=C=NC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(N=C=S)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a stirred solution of 28.4 parts of 4-isothiocyanato-1-(phenylmethyl)piperidine in 315 parts of methylbenzene are added dropwise 41 parts of (phenylmethyl) carbonochloridate at room temperature. Upon completion, the whole is heated to reflux and stirring is continued overnight at reflux temperature. The reaction mixture is cooled and the solvent is evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 32 parts (97%) of (phenylmethyl) 4-isothiocyanato-1-piperidinecarboxylate as a residue.
Reaction SMILES: CC1C=CC(C)=CC=1.O.O.O.O.C([O-])(=[O:15])C.[Co+2:17].C([O-])(=[O:20])C.[Br-].[K+].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)(=O)C>[OH2:15].[OH2:20].[C:24]([O-:29])(=[O:28])[C:25]([O-:27])=[O:26].[Co+2:17]
Reactant: CC(=O)[O-]
Reactant: O=C(O)C(=O)O
Agent: [Co+2]
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: O=C([O-])C(=O)[O-]
Yield: 100.7 %

Procedure:
The experiment described in Example 8 was performed with the use of 200 g of p-xylene, 1000 g of acetic acid, 10 g of cobalt acetate tetrahydrate (corresponding to 2.37 g of cobalt) and 2.75 g of potassium bromide (corresponding to 1.86 g of bromine). After a reaction time of 252 minutes and an oxygen absorption of 147.2 liters, 294.5 g of terephthalic acid was obtained. After the addition of 4.7 g of oxalic acid, 7.4 g of cobalt oxalate dihydrate was isolated from the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5].[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:44][C:45]#[N:46])=[N:41][C:42]=1Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:42]2[C:37]([Cl:36])=[CH:38][CH:39]=[C:40]([CH2:44][C:45]#[N:46])[N:41]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)n(-c2ccccc2)n1
Reactant: N#CCc1ccc(Cl)c(Cl)n1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3nc(CC#N)ccc3Cl)ccc2Cl)n(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a degassed solution of ethyl 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Preparation 5, 1.01 g, 1.34 mmol) and 2-(5,6-dichloropyridin-2-yl)acetonitrile (Preparation 59, 300 mg, 1.60 mmol) in dioxane (10 mL) was added Na2CO3 (213 mg, 2.01 mmol), water (1 drop) and Pd(PPh3)4 (144 mg, 0.134 mmol). The reaction was further degassed and heated to 80° C. for 1 hour. Further water (1 mL) was added and heating continued for 5 hours before cooling to room temperature. The reaction was filtered through Celite washing through with EtOAc, and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-100% MeCN in water with 0.1% formic acid to afford the title compound (360 mg, 49%).