Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[Cl-:11].[CH3:12][N:13]([CH3:39])[C:14]1[CH:38]=[CH:37][C:17]([CH:18]=[N:19][N+:20]2[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:21]=2[CH3:36])=[CH:16][CH:15]=1.CCOCC>CN(C)C=O>[Cl-:11].[CH3:35][N:33]([CH3:34])[C:30]1[CH:31]=[CH:32][C:27]([CH:26]=[N:25][N+:22]2[CH:23]=[CH:24][N:20]([N:19]=[CH:18][C:17]3[CH:16]=[CH:15][C:14]([N:13]([CH3:12])[CH3:39])=[CH:38][CH:37]=3)[C:21]=2[CH:36]=[CH:4][N:5]([CH3:7])[CH3:6])=[CH:28][CH:29]=1
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: CCOC(OCC)N(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 96 h

Procedure:
73.5 g of N,N-dimethylformamide diethyl acetal are added to 20.5 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride in 400 ml of dry dimethylformamide. After stirring at 50° for 4 days, the mixture is left to cool. Then, 250 ml of ether are added thereto and the product is removed by filtration and is recrystallized from dry ethanol. There is obtained 1,3-bis[[p-(dimethylamino) benzylidene]amino]-2-[2-(dimethylamino)vinyl]imidazolium chloride of melting point 265° (decomposition).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13](=O)O[C:10]2=[O:11].CS(C)=O>O>[CH3:13][N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[C:10](=[O:11])[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 12.3 g. of L-proline, 17.7 g. of N-mthyl isatoic anhydride and 100 ml. of dimethyl sulfoxide is heated on a steam bath for 40 minutes. The mixture is cooled and diluted with 250 ml. of cold water. The precipitate is recovered by filtration, washed with water and then ether, air dried and then recrystallized from ethanol yielding the intermediate L-1-(N-methylanthrailoyl)proline, melting point 140°-142°C., [α]D25 -165°C. (1.1%, methanol).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([CH:15]([C:25]([NH2:27])=[O:26])[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:25]([NH2:27])=[O:26])[C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=C(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
One hundred milligrams (0.2744 m mol) of 4-[(1-(2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid in 5 ml of absolute ethanol were hydrogenated in the presence of 50 mg of palladium/charcoal (10%) at 20° C. and at a hydrogen pressure of 1 bar under shaking. After 1.5 hours the catalyst was filtered off, and the filtrate was evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH3:33])[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1F
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1F

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.04 min; Mass spectrum (ESI+): m/z=455 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:25])=[O:24]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 0.67 h

Procedure:
Piperidine (5.50 ml, 55.5 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 7 ml) solution of 1-chloro-2-nitro-4-(trifluoromethyl)benzene (5.00 g, 22.4 mmol, commercially available product). The resulting mixture was stirred for 40 minutes. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200 g, hexane/ethyl acetate=8/1). Thus, 1-[2-nitro-4-(trifluoromethyl)phenyl]piperidine (6.13 g, quant.) was yielded as an orange-colored solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([C:33]#[C:34][Si](C)(C)C)[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([O:27][CH3:28])=[CH:16][N:15]=2)=[N:6]1>O1CCCC1>[C:33]([C:31]1[CH:30]=[CH:29][C:3]([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[C:17]([O:27][CH3:28])=[CH:16][N:15]=3)=[N:6]2)=[C:2]([F:1])[CH:32]=1)#[CH:34]
Reactant: COc1cnc(-c2nn(Cc3ccc(C#C[Si](C)(C)C)cc3F)c3ccccc23)nc1Nc1ccncc1
Solvent: C1CCOC1
Product: C#Cc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
37.3 mg of 2-(1-{2-fluoro-4-[(trimethylsilyl)ethynyl]benzyl}-1H-indazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (0.071 mmol, 1. eq.) were dissolved in 1.0 ml of dry tetrahydrofuran. 71 μl of a 1 M N,N,N-tributylbutan-1-ammonium fluoride in tetrahydrofuran (0.071 mmol, 1 eq.) were added under nitrogen atmosphere and stirred at room temperature for 18 hours. Then the mixture was partitioned between a aqueous half saturated sodium hydrogen carbonate solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC in ethyl acetate/methanol 7:3 to yield 23.2 mg (0.05 mmol, 68.4%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(OC)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of methyl 4-methoxy-2-(4-fluorophenyl)benzoate (9.8 g.) in methanol (75 ml.) was added 2N aqueous sodium hydroxide solution (45 ml.) and the mixture heated at reflux for 1.5 hours. The reaction was cooled to ambient temperature, filtered and the filtrate concentrated to remove the methanol. The residual aqueous phase was washed with ether, acidified to pH 1 using concentrated hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried and the solvent removed to give 4-methoxy-2-(4-fluorophenyl)benzoic acid (Compound (xxix) in Scheme 3) as a white solid (7.7 g), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.CS(O[CH2:27][C:28]([CH3:39])([CH3:38])[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:27][C:28]([CH3:39])([CH2:38][O:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:8]1[N:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]3=[N:10][N:9]=1)[CH:20]=[CH:19]2)[CH2:29][NH:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COS(C)(=O)=O
Reactant: Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1ccn2c(-c3ccc4cccc(OCC(C)(C)CNC(=O)OC(C)(C)C)c4n3)nnc2c1
Temperature: 50 °C
Yield: 42.1 %

Procedure:
A mixture of 2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (prepared according to Example 1; 50 mg, 0.18 mmol), 3-(tert-butoxycarbonylamino)-2,2-dimethylpropyl methanesulfonate (102 mg, 0.36 mmol) and cesium carbonate (118 mg, 0.36 mmol) in dimethylacetamide (2 mL) was heated to 50° C. overnight. The mixture was concentrated under reduced pressure and purified by successive silica gel chromatography, eluting with 1:9 methanol/dichloromethane and a gradient of dichloromethane to 1:9 methanol/dichloromethane. The residue was then purified by preparative thin layer chromatography eluting with 3:7 acetone/dichloromethane to provide 35 mg (42%) of desired product as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[N:32][N:33]([CH:35]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]2)[CH:34]=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>O1CCOCC1>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]4)[CH:34]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(N)cn2)C1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), Cs2CO3 (0.291 g, 0.892 mmol) and tert-butyl 3-(4-amino-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.142 g, 0.595 mmol) in dioxane (3 mL) was sonicated for 10 minutes. Xantphos (6.9 mg, 12 μmol) and Pd(II) acetate (1.3 mg, 5.9 μmol) were added to the suspension and the mixture was irradiated in the microwave for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-40% MeOH in EtOAc) to give the title compound A18 as a yellow oil (110 mg, 69%). LCMS-A: rt 6.349 min; m/z 538.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1ccc(O)cc1)c1nc(Cl)nc2ccccc12
Temperature: -20 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.334 mmol) in 30 ml dichloromethane cooled at −20° C. was added slowly 60 μl of BBr3 (0.668 mmol). The reaction mixture was stirred at −20° C. for 2 h then it was warmed to room temperature. It was stirred another 2 h at this temperature. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with cold 5% sodium bicarbonate. The organic phase was dried and concentrated. The residue was purified by a small silica column using ethyl acetate and hexane (1:3) as eluents to give the product (57 mg, 57%). 1H NMR (CDCl3): 7.65-7.56 (m, 2H), 7.04-6.87 (m, 5H), 3.59 (s, 3H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:31][C:30]4[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(OC(F)(F)F)cc3)(CC1)CC2
Yield: 37.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.3 mg) and 4-trifluoromethoxyaniline (60.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-trifluoromethoxyphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (28.2 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([N:27]([CH3:36])[CH3:26])=[CH:29][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(c1ccccc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccccc1)N1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Temperature: 70 °C
Reaction time: 0.02 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-(1-phenylethyl)piperazin-1-yl)pyridin-2-amine (0.038 g, 0.10 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.023 g, 0.15 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 6 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column, which was eluted with 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The obtained yellow solid was suspended in dichloromethane (2 ml), and then a solution of HCl in methanol (1.25 M; 0.8 ml) was added. The mixture was stirred for approximately 1 min, and then diethyl ether was added. The yellow precipitate was collected by filtration, washed with ether to afford the title compound as a hydrochloride salt. (0.013 g); 1H-NMR (500 Mz, CD3OD) 1.90 (d, J=5.43 Hz, 3H, CHCH3), 3.43 (m), 3.96 (m), 4.12 (m) (8H, piperazine N(CH2)2), 3.21 (s, 6H, N(CH3)2), 4.65 (m, 1H, NCHCH3), 7.14 (d, J=7.30 Hz, 2H) and 8.14 (d, J=7.32 Hz, 2H) (3,5-C6H4—NMe2 and 2,6-C6H4—NMe2) 7.55 (m, 3H) and 7.66 (m, 2H) (ArH), 8.41 (s, 1H, imidazo[4,5-b]pyridine 5-H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](I)[CH3:25]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:24][CH3:25])[CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCI
Reactant: COC(=O)c1cc(Cl)cc(NCC(C)C)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(CC(C)C)c1cc(Cl)cc(C(=O)OC)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-chloro-3-(isobutyl amino)-2-methylbenzoate (1.0 g, 3.9 mmol) in dry DMF (10 mL), cesium carbonate (2.55 g, 7.82 mmol) and ethyl iodide (6.09 g, 39.1 mmol) were added. The resulting reaction mass was heated at 80° C. for 12 h. On completion, the reaction mass was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give crude material which then used for next step as is (10 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[O-][Cl:15].[Na+]>CCO>[Cl:15][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[NH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc2cn[nH]c2cc1F
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc2c(Cl)n[nH]c2cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
6-Fluoro-5-nitroindazole (850 mg, 4.693 mmol, 1.0 equiv) was dissolved in 20 mL EtOH, NaOCl (10 mL, 164.26 mmol, 35 equiv) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vacuo to remove EtOH was then diluted with EtOAc and water. The phases were separated, and the organic phase was washed once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (10-100% EtOAc in Hexanes) to provide 583 mg (58%) of the title compound as a light orange solid. MS (ES+) m/e 216 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:46][C:47]([F:62])([F:61])[C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57](O)=[CH:56][CH:55]=2)=[CH:50][CH:49]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:13][C:57]2[CH:56]=[CH:55][C:54]([C:51]3[CH:52]=[CH:53][C:48]([C:47]([F:46])([F:61])[F:62])=[CH:49][CH:50]=3)=[CH:59][CH:58]=2)[CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: CCC(O)c1ccc(C(=O)OC)cc1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-propyl)-benzoic acid methyl ester (300 mg, 1.55 mmol) in toluene (10 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 585 mg, 2.32 mmol) at 0° C., followed by the addition of tributylphosphine (0.58 mL, 2.32 mmol) and 4′-trifluoromethyl-biphenyl-4-ol (442 mg, 1.86 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 hours at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid (570 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=O)[NH:16][C:15]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:24](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1.O>[C:19]([C:17]1[NH:16][C:15](=[O:22])[N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:18]=1)(=[O:21])[NH2:24]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)[nH]c2=O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(N)=O)[nH]c2=O)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (355 mg, 1.140 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL,) and N,N-dimethylformamide (15 μl, 0.194 mmol). Mixture was cooled to −10° C. Oxalyl chloride (150 μL, 1.714 mmol) was added to the mixture drop-wise. Reaction mixture was warmed to room temperature and held with stirring for 1 hour. Another 60 μL of oxalyl chloride was added to the mixture. Reaction stirred at room temperature for 30 minutes. Mixture was cooled to −10° C. Ammonia gas was bubbled through the mixture for 5 minutes. Reaction was held at −10° C. with stirring for 30 minutes. Mixture was warmed to room temperature and then diluted with water. Material was extracted three times with ethyl acetate and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as off-white solid in 79% yield. MS (M−H)−=309.2.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[C:13]1=[O:16])[CH:18]=[CH:19][CH3:20]
Reactant: O=C1CCc2ccc(-c3ccccc3)cc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Yield: 72 %

Procedure:
A solution of 13.2 g of 6-phenyl-1-indanone, 11 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110ml of 2,2-dimethoxy-propane was boiled under reflux for 48 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 12.0 g (72%) of (RS)-2-(2-buten-1-yl)-6-phenyl-1-indanone was obtained as a light yellow solid which was used without further purification in the next reaction.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=[C:7]([N:17]=[C:18]=[S:19])[N:6]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])[N:8]=[C:7]([NH:17][C:18](=[S:19])[N:23]([CH3:22])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)[N:6]=1
Reactant: FC(F)(F)COc1cc(OCC(F)(F)F)nc(N=C=S)n1
Reactant: CNc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CN(C(=S)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a solution of 4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl isothiocyanate (6.87 mmol) in CH2Cl2 (10 mL) was added N-methyl-4-trifluoromethylaniline (6.87 mmol) and the resulting solution was stirred at room temperature. After 18 h the solvent was evaporated and the crude material purified by chromatography (silica, hexane/EtOAc) to afford 131 as a yellow solid (2.15 g, 62% yield): m.p. 109-111° C.; 1H NMR (CDCl3) δ 7.76 (d, 2H, J=8.5), 7.46 (d, 3H, J=8.5 Hz), 5.96 (s, 1H), 4.77-4.68 (q, 4H, J=8.5 Hz); ESI/MS 509 (M+H), 507 (M−H).