Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)C(C)C)(C)C.Cl[C:17](OC1C=CC([N+]([O-])=O)=CC=1)=[O:18].[C:29]1([C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:35]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:36]=[CH:37][C:38]([CH2:39][NH:40][C:17](=[O:18])[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:41][CH:42]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC(F)(F)F
Reactant: NCc1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2ccccc2)cc1)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.119 ml (1.64 mmol) of 2,2,2-trifluoroethanol and 0.306 ml (1.49 mmol) of N,N-diisopropylethylamine are added, dropwise and at ambient temperature, to a solution of 0.3 g (1.49 mmol) of para-nitrophenyl chloroformate in 15 ml of methylene chloride. The mixture is stirred at ambient temperature for 2 h, and then 0.275 g (1.5 mmol) of 4-phenylbenzylamine is added. N,N-Diisopropylethylamine is subsequently added, dropwise and at ambient temperature, until the precipitate which has formed disappears. The transparent solution thus obtained is stirred at ambient temperature for 1 h. The reaction medium is diluted with a further 10 ml of methylene chloride and washing is carried out with a saturated aqueous ammonium chloride solution and with a saturated aqueous sodium chloride solution. The phases are separated and the organic phase is dried over sodium sulfate. The product is filtered, the filtrate is concentrated under reduced pressure and the residue is purified by silica gel chromatography with methylene chloride.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O+]=1.[CH2:30]([NH2:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(N(CC)CC)C.N>C(Cl)(Cl)Cl.C(O)(=O)C>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N+:44]=1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCc1cc(C)cc(C)[o+]1
Reactant: CCCCCCCCCCCCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCc1cc(C)cc(C)[n+]1CCCCCCCCCCCCCC
Yield: 26 %

Procedure:
2,4-Dimethyl-6-tetradecylpyrylium hexafluorophosphate (10, n=13, 1.5 g, 3.33 mmol) was dissolved in 15 mL chloroform and treated with 0.71 g (3.33 mmol) of tetradecylamine (11, m=13). Triethylamine (0.5 mL) was then added to the brown-yellow solution, which was subsequently refluxed for 5 minutes, treated with 1 mL of acetic acid and refluxed for another hour. The homogenous mixture was treated with 0.2 mL of concentrated aqueous ammonia, refluxed for 5 min., cooled and extracted with 10 mL of water to solve the precipitated inorganic salts. After separation, the chloroform layer was dried on sodium sulfate and evaporated to dryness to yield 2.00 g of crude product. This product was purified by means of flash chromatography (Silica gel 60) using a 20/80 methanol/chloroform (v/v) mobile phase to yield 0.56 g (22%) of pure product, which was recrystallized from ethanol to yield 0.54 g of crystalline compound (12, m=n=13).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[BrH:10].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Br-:10].[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCc1ccccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Solvent: CC#N
Product: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
2-Hydroxybenzyl alcohol was treated with triphenylphosphine hydrobromide in acetonitrile as described in Example 1 to yield [(2-Hydroxyphenyl)methyl]triphenylphosphonium bromide.
Reaction SMILES: C(O[C:6]([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:31])=[CH:21][N:22]=[C:23]([O:28][CH2:29][CH3:30])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)C)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[CH3:6][NH:8][C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:31])=[CH:21][N:22]=[C:23]([O:28][CH2:29][CH3:30])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH2:11]1.[F:32][C:33]([F:38])([F:37])[C:34]([O-:36])=[O:35]
Reactant: CCOc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@H](N(C)C(=O)OC(C)(C)C)C3)cccc12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@H](NC)C3)cccc12
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Intermediate 38a (141 mg) obtained in Step A was dissolved in a solution of trifluoroacetic acid (0.9 ml, Aldrich) in dichloromethane (2.1 ml), and the solution was stirred at room temperature 5 hours. The solvent was evaporated under reduced pressure to obtain the title compound as trifluoroacetate (145 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])=[CH:3][C:2]=1[Cl:1]
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A mixture of (3,4-dichlorophenyl)boronic acid (500 mg, 2.62 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (501 mg, 2.88 mmol), K2CO3 (723 mg, 5.24 mmol) and Pd(PPh3)2Cl2 (36 mg, 0.052 mmol) in THF (2 mL) and H2O (1 mL) was heated at 80° C. in a sealed tube for 3 hours. The mixture was cooled to rt and partitioned between EA (20 mL) and H2O (20 mL). The aqueous layer was extracted with EA (20 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with PE to give 1,2-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)-benzene (400 mg, 63.3% yield) as colorless oil.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:35][OH:36])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.O[C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1>O1CCCC1.CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:35][O:36][C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.4 %

Procedure:
A solution of 6.6 g of 1,1'-(azodicarbonyl)dipiperidine in 10 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous dimethylformamide was added dropwise to a mixture of 6.5 g of 1-t-butoxycarbonyl-2-hydroxymethylindoline (prepared as described in preparation 3), 6.5 ml of tributylphosphine, 12.2 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in European Patent Publication No. 549 365A1] and 100 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for about 20 hours. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.70 g of the title compound, melting at 85.4°-87.2° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrCCBr.C([O-])([O-])=O.[K+].[K+]>CCCCCC.C1COCC1>[CH2:6]([N+:13]12[CH2:14][C:15]([C:18]([O-:20])=[O:19])([CH2:16][CH2:17]1)[CH2:2][CH2:1]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C([O-])C12CC[N+](Cc3ccccc3)(CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To DIPA (3.6 mL) was added dropwise a 2.64 M solution of n-butyl lithium in hexane (8.93 mL) at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added ethyl 1-benzyl-pyrrolidine-3-carboxylate (5.0 g), followed by stirring for 30 minutes. To the reaction mixture was added dropwise a solution of 1,2-dibromoethane (6.05 g) in THF, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The aqueous layer was concentrated under reduced pressure, and to the residue was added EtOH, followed by stirring at room temperature for 30 minutes. The insolubles were removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added EtOH, followed by stirring at room temperature for 10 minutes. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1-benzyl-1-azoniabicyclo[2.2.1]heptane-4-carboxylate (3.25 g) as a colorless solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH2:27])[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:27][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:26][CH2:25]1
Reactant: COC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: COC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αS)-α-amino-cyclopropanepropanoic acid methyl ester hydrochloride (1:1) (CAN 206438-31-5) as starting materials, LC-MS (UV peak area/ESI) 100%, 359.153 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: Cc1cccnc1N
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ncccc2C)c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 26.8 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 2-amino-3-methylpyridine (45 mg, 0.417 mmol) was added portionwise. The resulting mixture was stirred at room temperature for five days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield the title compound (26 mg, 27% yield).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][C:7]([O:14][CH3:15])=[CH:6][C:3]=1[CH:4]=O.[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C[Si]([C:29]#[N:30])(C)C.[NH4+]=[S:32]>CO.Cl.NC(N)=N.C(OCC)(=O)C.O1CCCC1>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([NH:16][CH:4]([C:3]2[CH:6]=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][OH:13])[C:2]=2[F:1])[C:29]([NH2:30])=[S:32])=[CH:18][CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(N)cc1
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc(C=O)c(F)c(OCCO)c1
Agent: Cl
Agent: N=C(N)N
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Temperature: 40 °C
Reaction time: 19 h

Procedure:
Under nitrogen atmosphere, to a solution of the crude product containing 2-fluoro-3-(2-hydroxyethoxy)-5-methoxybenzaldehyde (16.68 g, 77.9 mmol), 4-aminobenzonitrile (9.20 g, 77.9 mmol), and guanidine hydrochloride (372 mg, 3.9 mmol) in methanol (132 mL), trimethylsilylcyanide (12.09 g, 116.9 mmol) was added at room temperature, and the resulting mixture was stirred at 40° C. for 19 hours. After cooling the mixture, tetrahydrofuran (132 mL) was added thereto under water cooling, and 20% aqueous ammonium sulfide solution (133 mL) was added dropwise to the resulting mixture, after which the resulting mixture was stirred at room temperature. After completion of the reaction, ethyl acetate and 5% saline were added to the reaction mixture, and the resulting mixture was extracted. The organic layer was washed with 5% saline and then concentrated under reduced pressure. Methanol (100 mL) was added to the residue obtained, and the resulting mixture was concentrated under reduced pressure. Further, methanol (100 mL) was added to the residue obtained, and the resulting mixture was concentrated under reduced pressure. Methanol (120 mL) was added to the residue obtained, and the resulting mixture was stirred overnight at room temperature. The precipitated solid was filtered and dried to obtain the captioned compound (20.46 g) as a pale purple solid.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([O-])=O>CCO.C(Cl)Cl.[Pd]>[CH:9]1[C:8]2[C:13](=[C:14]([NH2:16])[N:15]=[C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]3=2)[N:12]=[CH:11][CH:10]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc2c(c1)nc(N)c1ncccc12

Procedure:
A mixture of 8-nitrobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Pd/C (wet, 10% wt) in EtOH was stiffed under H2 balloon overnight. The reaction mixture was diluted with DCM. The insoluble solid was filtered off through celite, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was washed with acetone to give benzo[f][1,7]naphthyridine-5,8-diamine as an off white solid: 1H NMR (methanol-d4): δ 8.73 (dd, 1H), 8.71 (dd, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 6.86 (d, 1H), 6.82 (dd, 1H). LRMS [M+H]=211.1.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])=O>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=4)[C:25]#[N:26])[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Product: N#Cc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 3-formylbenzonitrile was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:41][O:42][C:43]1[C:52]([C:53](O)=[O:54])=[C:51]([CH3:56])[C:50]2[C:45](=[CH:46][C:47]([C:57]([F:60])([F:59])[F:58])=[CH:48][CH:49]=2)[N:44]=1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:53]([C:52]2[C:43]([O:42][CH3:41])=[N:44][C:45]3[C:50]([C:51]=2[CH3:56])=[CH:49][CH:48]=[C:47]([C:57]([F:59])([F:60])[F:58])[CH:46]=3)=[O:54])=[CH:4][CH:3]=1
Reactant: COc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
87 μl (0.8 mmol) 4-fluorobenzylamine, 266 mg (0.7 mmol) HATU and 281 μl (2.0 mmol) NEt3 were added consecutively to a solution of 199 mg (0.7 mmol) 2-methoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid in THF (5 ml) and the solution was then stirred for 72 h at RT. The solution was subsequently diluted with EtOAc and washed with a 4N aq. NH4Cl sol., a 1M aq. Na2CO3 sol. and brine. The organic phase was dried over MgSO4, filtered through silica gel and concentrated in a vacuum. After crystallisation (EtOAc/hexane 1:2) of the residue, 161 mg (0.4 mmol, 59%) N-[(4-fluorophenyl)-methyl]-2-methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 5) was obtained. MS: m/z 393.1 [M+H]+.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:25]([P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: CCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCP(=O)(OCC)OCC

Procedure:
100 g (590 mmol) of triethyl phosphite and 164 g (590 mmol) of 1-bromotetradecane are heated on a column connected to a descending condenser. Bromoethane distills out at a bath temperature of 170° C.; the mixture is then distilled under high vacuum, resulting in the product of boiling point 145° C./0.03 mmHg which is pure by 1H NMR.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]([F:30])([F:29])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:12][CH:13]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(CCC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCC(F)(F)F)cc3)cc2)C1
Yield: 11.7 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (12 ml) was treated with 4-(3,3,3-trifluoro-propyl)-benzenesulfonyl chloride (214 mg, 0.78 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (26 mg, 11%) as a colourless gum.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[O:13]1CC[CH2:15][CH2:14]1>CCCCCC>[CH2:11]=[CH:10][CH2:9][CH2:8][C:14](=[O:13])[CH2:15][CH2:7][CH:5]=[CH2:6]
Reactant: CC(C)NC(C)C
Reactant: C1CCOC1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: C=CCCC(=O)CCC=C
Temperature: -30 °C

Procedure:
To a solution of 16.0 g (158 mmol) of diisopropylamine in 150 ml of tetrahydrofuran at 0° C. was added 158 ml of a 1.0M solution of n-butyllithium in hexane. The reaction mixture was cooled to -30° C., and to it was added a solution of 20.2 g (144 mmol) of the title product of Example 62 in 75 ml of tetrahydrofuran. After 1.0 hour at -30° C., the mixture was cooled to -70° C. To the resulting mixture was then added 26.1 g of allyl bromide in 38 ml of tetrahydrofuran. After 10 minutes, the mixture was permitted to warm to room temperature, and after 2 hours, it was poured into brine. The aqueous layer was further extracted with diethyl ether. After drying the combined extracts over sodium sulfate followed by filtration, the solvent was removed and the residue distilled to give a crude product (8.53 g) which was used without further purification. A solution of 4.14 g of the crude material in 13 ml of tetrahydrofuran was added to a mixture of 2.57 g of diisopropylamine, 25.4 ml of a 1.0M solution of n-butyllithium in hexane, and 25 ml of tetrahydrofuran at -30° C. The resulting mixture was kept for one hour at -30° C., and thereafter 3.0 g of allyl bromide was added. After stirring overnight at room temperature, the mixture was poured into brine, the aqueous layer extracted with diethyl ether, and the combined organic solutions dried over sodium sulfate. After filtration, the solvent was removed, and the residue was then stirred overnight in a mixture of 50 ml of diethyl ether and 50 ml of 3N hydrochloric acid. The mixture was then poured into brine and the aqueous layer was further extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, and filtered. The solvents were removed by distillation through a Vigreaux column at atmospheric pressure. Distillation of the residue at 5 mm of pressure gave the title compound (719 mg), suitable for use in the next reaction step.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH:6]1[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>>[Br:32][CH2:2][CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH:6]1[CH3:11]
Reactant: CC1CC(=O)NC1CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1CC(=O)NC1CCCBr

Procedure:
A mixture of the title compound of EXAMPLE 235 is treated with triphenylphosphine and carbon tetrabromide by the method of EXAMPLE 224 to generate the title material.
Reaction SMILES: [C:1]([C:5]1C=C[C:8](C2C=CC=C(C3N=C(C)C4C(C=3)=CC([O:27]C)=C(OC)C=4)C=2)=[CH:7][CH:6]=1)(C)(C)[CH3:2].[O:32]1[CH2:37][CH2:36]O[CH2:34][CH2:33]1>>[CH3:34][CH2:33][O:32][C:37]([CH3:36])=[O:27].[CH3:2][CH2:1][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COc1cc2cc(-c3cccc(-c4ccc(C(C)(C)C)cc4)c3)nc(C)c2cc1OC
Reactant: C1COCCO1
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Yield: 77 %

Procedure:
3-(4′-(tert-Butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxy-1-methylisoquinoline (100 mg) and SeO2 (32 mg, 1.2 eq.) in 5 mL anhydrous dioxane were refluxed at 102° C. for 3 hours. Solution was then cooled to room temperature and filtered to remove precipitate. Resulting filtrate was concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a yellow solid (80 mg, 77% yield). 1H NMR (400 MHz) (CDCl3) δ 10.40 (s, 1H), 8.68 (s, 1H), 8.34 (m, 1H), 8.14 (s, 1H), 8.07 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 3H), 7.52 (t, J=16 Hz, 1H), 7.45 (d, J=8 Hz, 2H), 7.13 (s, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 1.32 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 196.81, 153.33, 152.83, 149.76, 141.84, 139.20, 138.29, 135.44, 129.26, 127.43, 126.95, 125.76, 125.59, 125.35, 122.19, 120.01, 104.99, 103.59, 56.29, 56.02, 34.57, 31.38.