Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O-])(O)=[O:10].[Na+].C=O.Cl>O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: OCc1ccc(O)c(Cl)n1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
2-Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO3 (19.5 g, 0.232 mole, 1.5 equ), and 150 mL of water are placed in a flask. The flask is placed in an oil bath at 90° C., and after 5 min, 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5 equ) is added in six unequal doses in the following order: 12 mL, 3×8 mL, then 2.2 mL all at 90-min intervals and then the final 2.3 mL after the reaction stirs for 15 h at 90° C. The reaction is stirred at 90° C. for another 4 h and then cooled by placing the flask in an ice bath. The pH of the reaction is then adjusted to 1 using 6N HCl. The reaction is stirred for 1.5 h in an ice bath allowing an undesired solid to form. The undesired solid is removed by filtration, and the filtrate is extracted seven times with EtOAc. The combined organic extracts are concentrated in vacuo, toluene is added to the flask and removed in vacuo to azeotrope water, and then CH2Cl2 is added and removed in vacuo to obtain 2-chloro-6-(hydroxymethyl)-3-pyridinol as a pale yellow solid (81% yield) sufficiently pure for subsequent reaction. MS (EI) for C6H6ClNO2, m/z: 159(M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.CI.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:15][CH:16]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Product: FC(F)(F)Oc1ccc(Nc2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reaction time: 24 h

Procedure:
A solution of 4,5-dichloro-1,2-phenylenediamine (2 mmol, 354 mg) and 4-trifluoromethoxyphenyl isothiocyanate (2 mmol, 325 μL) in CH2Cl2 (3 mL) was heated at 40° C. for 4 h. MeI (2.2 mmol, 137 μL) and DIEA (2.0 mmol, 348 μL) were added, and the reaction was brought to 40° C. for 24 h. The reaction mixture was partitioned between CH2Cl2 and brine. The organic phase was dried with Na2SO4 and concentrated in vacuo. Chromatography on silica eluting with 20-40% EtOAc in hexanes provided the product as a tan solid. 1H NMR (500 MHz, d6-DMSO) δ 11.2 (br s, 1H), 9.91 (s, 1H), 7.84 (m, 2H), 7.52 (br s, 1H), 7.34 (d, J=9 Hz, 2H). LC-MS (ESI, Method A): 2.96 min, m/z 362.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7](O)[CH2:8][N+:9]([O-:11])=[O:10].CCN(CC)CC.CS(Cl)(=O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1/[CH:7]=[CH:8]/[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])CC(O)c1ccsc1Br
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccsc1Br
Yield: 89 %

Procedure:
To a solution of 1-(2-bromothiophen-3-yl)-2-nitroethanol (3 g, 12.0 mmol), DMAP (146 mg, 1.2 mmol) and Et3N (2.4 g, 24.0 mmol) in DCM (30 mL) was added MsCl (2.4 g, 24.0 mmol) dropwise. The resulting mixture was then refluxed for 3 h. After cooling, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (2.5 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].Br.CS(C)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCOCC2)cc1NC(N)=S
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reaction time: 0.5 h

Procedure:
To a solution of 1 [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea (XI) in acetic acid is added hydrobromic acid, and stirring continued for about 30 min at 80° C. DMSO is then added dropwise and the reaction mixture stirred for a further 30 min at 80° C. The product (XII) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine is isolated by conventional means.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:22][NH2:23]>CCO>[Br:18][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][C:15]=1[CH3:17])[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:22][N:23]=1
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(C)c(Br)cc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1Br)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of 2-(6-bromo-7-methyl-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.192 g, 0.536 mmol) in EtOH (3 mL) was added anhydrous hydrazine hydrate (0.107 g, 2.144 mmol) and the mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% EtOAc in petroleum ether) to give 6-bromo-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as white solid (0.15 g, 90%). 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 7.46 (s, 1H), 7.02 (s, 1H), 4.86 (q, J=6.8 Hz, 1H), 4.60 (dd, J=12.8 Hz, 2H), 2.26 (s, 3H), 1.27 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[C:4]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]2)[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([N:8]=[C:9]([CH3:10])[C:16]3[N:12]2[CH:13]=[N:14][C:15]=3[CH3:17])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(F)cc1-n1cnc(C)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ncn2c1c(C)nc1ccc(F)cc12
Yield: 12.9 %

Procedure:
Reaction of intermediate 3A (13.4 g, 57.5 mmol), P2O5 (16.3 g, 115 mmol), and POCl3 (100 mL) provided the product 4A as an off-white powder (1.6 g, 22% yield). EIMS 216.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([C:8]([OH:10])=[O:9])[NH2:7])[CH2:4][CH2:3][CH2:2]1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[OH-].[Na+]>[CH2:15]([O:14][C:12]([NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: NC(CC1CCC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)NC(CC1CCC1)C(=O)O
Reaction time: 2 h

Procedure:
10 g (70 mmol) of 3-cyclobutyl-DL-alanine [A. Burger et al., J. Med. Chem. 6, 221 (1963)] is dissolved, in 70 ml of 2M NaOH solution, cooled to +5° C. and 11.1 ml (116.2 mmol) of ethyl chloroformate is added in drops with constant stirring. Stirring is continued for 2 hours at this temperature, and for further 2 hours at room temperature. The reaction mixture is then washed with 20 ml of diethyl ether and after acidifying the solution to pH1 extracted with 3×20 ml of ethyl acetate. The pooled extracts are washed with brine, dried over anhydrous sodium sulphate and the solvent is evaporated at a pressure of 2.0-2.5 kPa. The resulted oil is considered to be the pure product [Yield: 13.1 g (87%), Rf(7)=0.8] and is used without further treatment in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[N:6][CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ncc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 30 g of 5-chloropyridin-3-ol (232 mmol, 1 equivalent) were dissolved in 228 ml of concentrated sulphuric acid, and, at 0° C., 24 ml of concentrated nitric acid were added slowly. The reaction was warmed to RT and stirred overnight. The mixture was stirred into an ice/water mixture and stirred for another 30 min. The solid was filtered off, washed with cold water and air-dried. This gave 33 g (82% of theory) of the title compound, which were used without further purification for the next reaction.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH2:8][C@@H:9]1[C:31](=[O:32])[NH:30][C@@H:22]2[CH2:23][S:24][S:25][CH2:26][CH2:27][CH:28]=[CH:29][C@@H:13]([O:14][C:15](=[O:38])[CH2:16][NH:17][C:18](=[O:37])[C@@H:19]([CH:34]([CH3:36])[CH3:35])[NH:20][C:21]2=[O:33])[CH2:12][C:11](=[O:39])[NH:10]1)(C)(C)C.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[CH:34]([C@H:19]1[NH:20][C:21](=[O:33])[C@@H:22]2[NH:30][C:31](=[O:32])[C@@H:9]([CH2:8][CH2:7][C:6]([OH:40])=[O:5])[NH:10][C:11](=[O:39])[CH2:12][C@@H:13]([CH:29]=[CH:28][CH2:27][CH2:26][S:25][S:24][CH2:23]2)[O:14][C:15](=[O:38])[CH2:16][NH:17][C:18]1=[O:37])([CH3:36])[CH3:35]
Reactant: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](CC(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)N2)OC(=O)CNC1=O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](CC(=O)N[C@H](CCC(=O)O)C(=O)N2)OC(=O)CNC1=O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](CC(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)N2)OC(=O)CNC1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](CC(=O)N[C@H](CCC(=O)O)C(=O)N2)OC(=O)CNC1=O

Procedure:
To a solution of 9F (12 mg, 0.02 mmol) and Et3SiH (10 μL, 0.06 mmol) in CH2Cl2 (1.5 mL) was added TFA (150 μL, 2.0 mmol). After 6 h the solvent was removed and the residue purified by column chromatography on silica gel (10% methanol/CH2Cl2 then +1% AcOH) to give 1° F. (5.6 mg, 0.01 mmol, 55%) as a white solid: [α]25D −63.4 (c 0.25, MeOH); 1H-NMR (400 MHz, CD3OD) δ 7.5 (1×NH observed, d, J=7.5 Hz, 1H), 5.81 (dddd, J=16.8, 6.8, 4.8, 2.5 Hz, 1H), 5.75-5.67 (m, 2H), 4.62 (ddd, J=11.0, 8.0, 5.5 Hz 1H), 4.28 (d, J=17.5 Hz, 1H), 4.15 (dd, J=9.0, 6.0 Hz, 1H), 3.78 (d, J=17.5 Hz, 1H), 3.43 (d, J=10.5 Hz, 1H), 3.20-3.10 (m, 2H), 3.07-3.00 (m, 2H), 2.94-2.81 (m, 1H), 2.82 (dd, J=13.2, 2.2 Hz, 1H), 2.73-2.50 (m, 4H), 2.38 (q, J=7.0 Hz, 1H), 2.23-1.99 (m, 2H), 0.98 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H); 13C-NMR (100 MHz, CD3OD) δ 176.5 (C), 174.0 (C), 173.5 (C), 173.0 (C), 171.6 (C), 169.5 (C), 131.4 (CH), 131.3 (CH), 72.1 (CH), 66.0 (CH), 58.5 (CH), 57.0 (CH), 42.7 (CH2), 39.7 (CH2), 39.4 (CH2), 36.8 (CH2), 31.8 (CH2), 31.6 (CH2), 28.2 (CH3), 26.6 (CH2), 20.6 (CH3), 20.5 (CH3); LRMS (ES−) m/z 543 (100%, [M−H]−).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19](Cl)[C:9]=2[C:8]1=[O:23].[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1OB(O)O>>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])[C:9]=2[C:8]1=[O:23]
Reactant: Cc1ccccc1OB(O)O
Reactant: CSc1nc(Cl)c2c(n1)N(C)CCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Product: CSc1nc(-c2ccccc2C)c2c(n1)N(C)CCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Yield: 100 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-10-methyl-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 9; 1.25 g) was reacted with 2-methylphenylboric acid (410 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (1.39 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[C:9]=2[CH2:15][OH:16])=[C:4](F)[CH:3]=1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[C:10]([CH3:14])[N:11]=[CH:12][CH:13]=3)[CH2:15][O:16][C:4]=2[CH:3]=1
Reactant: Cc1nccc(-c2ccc(Cl)cc2F)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nccc2c1COc1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 170.9 %

Procedure:
To a solution of (4-(4-chloro-2-fluorophenyl)-2-methylpyridin-3-yl)methanol (70 mg, 0.278 mmol) in tetrahydrofuran (3 mL) at 0° C. was added NaH (33.4 mg, 0.834 mmol) portionwise. The solution was allowed to warm to room temperature and stirred for 5 h. The reaction mixture was quenched with ice cold water and diluted with EtOAc (15 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 8-chloro-4-methyl-5H-chromeno[3,4-c]pyridine (0.11 g, 0.475 mmol, 73% yield) as a brown solid. LCMS (ESI) m/e 232.00 [(M+H)+, calcd for C13H12ClNO 232.01]; LC/MS retention time (Method G): tR=1.00 min.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Pd]>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:13][CH:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1
Reaction time: 8 h

Procedure:
A stirred solution of ethyl 6-(6,7-diphenyl-1,8-naphthyridin-2-yl)hexanoate (step 2)(280 mg, 0.660 mmol) in EtOH (10 ml) under an atmosphere of argon was treated with 10% palladium on carbon (70.2 mg), purged three times with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture was filtered through Celite® (filter material) and the catalyst was washed with EtOAc (100 ml). The filtrate was concentrated in vacuo to yield the title compound as an off white solid. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:21])[C:15](=[CH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O>O>[O:21]=[C:14]1[C:11]2[C:10](=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[C:12]=2[Cl:13])[CH2:20][CH:15]1[CH2:16][CH:17]([CH3:18])[CH3:19]
Reactant: C=C(CC(C)C)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)CC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 60 °C
Yield: 85 %

Procedure:
[2,3-Dichloro-4-(2-methylene-4-methylvaleryl)phenoxy]-acetic acid (2.0 g., 0.006 mole) is added with stirring to concentrated sulfuric acid (10 ml.) and the mixture is heated at 60° C. for six hours. The reaction mixture is then cooled and poured into a mixture of ice and water (200 ml.) and the crude product which separates is ground in a mortar, filtered, washed with water and dried. After recrystallization from acetic acid (60 ml.) there is thus obtained 1.7 g. (85% yield) of (1-oxo-2-isobutyl-6,7-dichloro-5-indanyloxy)acetic acid, m.p. 191.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2)#[N:2].[NH4+].[OH-]>CN(C=O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2
Reactant: N#Cc1ccc2c(c1)CCC(NC(=O)c1ccc(-c3ccc(F)cc3)cc1)C2
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NCc1ccc2c(c1)CCC(NC(=O)c1ccc(-c3ccc(F)cc3)cc1)C2
Reaction time: 18 h
Yield: 94 %

Procedure:
A suspension of 4′-fluoro-biphenyl-4-carboxylic acid (6-cyano-1,2,3,4-tetrahydro-naphthalen-2-yl)-amide, 3, (1.430 g, 3.514 mmol), Raney-Ni (0.5 g) and 28% NH4OH (1.0 mL) in DMF (25 mL) is hydrogenated for 18 hours. The catalyst is removed by filtration and the filtrate concentrated in vacuo to afford 1.352 g (94% yield) of the desired product. 1H NMR (300 MHz, DMF-D7) δ 8.55 (d, J=7.5 Hz, 1H), 8.20 (d, J=8.7 Hz, 2H), 7.72-7.85 (m, 4H), 7.35 (t, J=9.3 Hz, 2H), 6.95-7.23 (br, 3H), 4.20-4.42 (m, 1H), 3.12-3.24 (br, 2H), 2.90-3.08 (m, 4H), 2.11-2.25 (m, 1H), 1.90 (m, 1H); 13C NMR (75 MHz, DMF-D7) δ166.2, 164.8, 142.6, 136.8, 135.8, 134.5, 133.8, 129.6, 129.4, 129.3, 128.5, 127.0, 125.6, 116.4, 116.1, 64.0, 46.9, 34.2, 28.7, 28.0; 19F NMR (282 MHz, DMF-D7) δ 46.6; LRMS: 375.3 (M+H), 358.3 (M+H−NH3), HRMS: calcd: for C24H24FN2O 375.1873, found: 375.1866.
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:7]([NH2:16])=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2].O[CH:18]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)S([O-])(=O)=O.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH:1]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:8][C:7]=2[N:16]=[C:18]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1ccc(C(F)(F)F)cc1N
Reactant: O=S(=O)([O-])C(O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)n1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A mixture of 0.76 g of N1-sec-butyl-4-trifluoromethylbenzene-1,2-diamine, 0.84 g of sodium hydroxy-pyridin-4-yl-methanesulfonate and 17 ml of DMF was stirred for 1 hour at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured a saturated sodium hydrogen carbonate aqueous solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.91 g of 1-sec-butyl-2-pyridin-4-yl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 201).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>O1CCCC1.C1OCCOCCOCCOCCOC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:34]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)(=[O:35])=[O:36])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: COc1ccc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2C#N)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) in tetrahydrofuran (2 mL), 15-crown-5 (0.13 mL) and 6-methoxypyridine-3-sulfonyl chloride (135 mg) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was diluted with ice water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:3) to give the title compound as a pale-yellow oil (yield 235 mg, 97%).
Reaction SMILES: [CH2:1]=[CH2:2].FF.[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:5]([CH3:11])=[CH:6][CH:7]=1)[CH3:2]
Reactant: C=C
Reactant: Cc1ccccc1
Agent: FF
Product: CCc1ccc(C)cc1
Yield: 27.9 %

Procedure:
The same reactor used in Example 4 was charged with a feedstock containing a (3.6 wt.%, 10.4 mol %) concentration of ethylene in toluene. At a reaction temperature of 100° C., 5.95 g (9.0 mL) of a catalyst analyzed to contain 19.71 wt.% fluorine gave 49.4% ortho-, 22.7% meta-, and 27.9% para-ethyl-methyl-benzene with 44.4 mol % conversion, compared to 17.1 mol % conversion for a control catalyst in which the polymer had not been fluorinated.
Reaction SMILES: C([O:5][C:6](=[O:54])[C:7]([O:10]/[N:11]=[C:12](/[C:41]1[N:42]=[C:43]([NH:46]C(OC(C)(C)C)=O)[S:44][CH:45]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH2:30][C@@H:29]([CH2:31][NH:32]C(OC(C)(C)C)=O)[O:28][C:27]1=[O:40])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C@H:29]1[O:28][C:27](=[O:40])[N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:54])=[O:5])/[C:41]3[N:42]=[C:43]([NH2:46])[S:44][CH:45]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:22])=[O:23])[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1C[C@@H](CN)OC1=O)c1csc(N)n1)C(=O)O
Yield: 78.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((R)-5-(((tert-butoxycarbonyl)amino)methyl)-2-oxooxazolidin-3-yl)methyl)-4-oxoazetidine-1-sulfonic acid (160 mg, 0.199 mmol), DCM (1.5 mL) and TFA (500 μL, 6.49 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (85.8 mg, 78%) as a white powder. LCMS: m/z=548.0 (M+1); 1H NMR (400 MHz, D2O) δ ppm 6.93 (s, 1H), 5.23 (d, J=5.6 Hz, 1H), 4.76-4.69 (m, 1H), 4.54-4.49 (m, 1H), 3.84 (t, J=9.6 Hz, 1H), 3.56 (dd, J=14.8, 9.6 Hz, 1H), 3.41-3.34 (m, 2H), 3.21-3.11 (m, 2H), 1.34 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:17]1([CH2:23][C:24](=[NH:28])OCC)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:24](=[NH:28])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1
Yield: 15.6 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.5 g, 12.5 mmol) and ethyl phenylacetimidate hydrochloride (2.5 g, 12.5 mmol) in ethanol (100 ml) was heated under reflux for 1 hour. The solvent was evaporated in vacuo, and the residue taken up in chloroform, washed with aqueous sodium bicarbonate, dried and the chloroform evaporated. Treatment with charcoal and recrystallisation from ethyl acetate/petroleum ether gave the product (0.62 g), m.p. 114°-116° C.