Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:42]I>ClCCl>[I:42][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
tert-Butyl [4-(2-hydroxyethyl)phenyl]carbamate (6.45 g, 27.18 mmol) in dichloromethane (20 mL) was added drop-wise to a solution of imidazole (2.04 g, 30.0 mmol), triphenylphosphine (8.60 g, 32.8 mmol), and iodine (8.28 g, 32.6 mmol) in dichloromethane (80 mL) at 0° C. The reaction was allowed to warm to rt and was stirred overnight at room temperature. The reaction was cooled to 0° C. and quenched with water (100 mL). The organic layer was separated, washed with saturated aqueous sodium thiosulfate (100 mL), water (100 mL), and brine (100 mL). The organics were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified via flash chromatography using an Analogix SF40-150 g column eluting with 30% EtOAc in heptane to afford the title compound as a white solid (8.16 g, 86.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9H) 3.13 (t, J=8.00 Hz, 2H) 3.27-3.35 (m, 2H) 7.12 (d, J=8.59 Hz, 2H) 7.32 (d, J=8.59 Hz, 2H).
Reaction SMILES: O1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[S:5])[CH2:3][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(O)(=O)C.[Zn]>[S:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH:4]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: S=C1CC(c2ccccc2)Oc2ccccc21
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc(C2CCc3ccccc3S2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
Thioflavanone (10.0 g) was dissolved in acetic acid (300 ml) and concentrated hydrochloric acid (30 ml) and added to zinc amalgam prepared from zinc powder (100 g.) and mercuric chloride (8.0 g.) The reaction mixture was stirred at room temperature for 3 hr., then allowed to stand overnight. The reaction mixture was filtered and the filtrate diluted with water and extracted with toluene. The toluene extract was washed with water, dried and evaporated. Trituration of the residue with ethanol gave, on filtration, thioflavan (2.55 g) m.pt. 45°-49°-Recrystallisation of a sample from ethanol gave pure thioflavan m.pt 55°-56°.
Reaction SMILES: C(OC(=O)N[C@H](C1NC=CN=1)CC1C=CC=CC=1)(C)(C)C.C[O:23][C:24](=O)[C@@H:25]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:37]([O:36][C:34](=[O:35])[NH:33][C@@H:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:24]=[O:23])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 106.6 %

Procedure:
[(S)-1-(1H-imidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester: To (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester (100.0 g, 0.35 mol) in toluene (1 L) at −78° C. was added DIBAL-H (2M solution in toluene, 322 mL, 0.64 mol) dropwise and the reaction stirred at −78° C. for 30 min. The reaction was quenched with methanol (40 mL) and the mixture was stirred with NH4Cl (350 g in 100 mL of water) for 10 min. The solution was filtered through Celite® and the aluminum salts were washed with cold ethyl acetate and water. The filtrate layers were separated and the organic layer was dried over sodium sulfate and concentrated at a temperature below 35° C. to provide ((S)-1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (93 g). To this intermediate (93 g, 0.37 mol) in methanol (1 L) was added glyoxal trimeric dihydrate (39.2 g, 0.18 mol), followed by 2M NH3 in methanol (838 mL) and the reaction mixture was stirred at rt for 48 h. The reaction mixture was evaporated and the crude was purified by column chromatography followed by crystallization from hexane to provide 92C as a grey solid (23 g, 23%). 1HNMR (CDCl3, 400 MHz) δ: 9.8 (bs, 1H), 7.27 (m, 3H), 7.21 (m, 2H), 6.95 (d, 2H), 5.32, 4.91 (2d, 2H), 3.32 (d, 2H), 1.3 (s, 9H). LCMS m/z 287 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:19][C:18]1[C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccnc1N
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: CN(C)C=O
Product: Cc1cccnc1NC(=O)N=C1NC(=O)CN1C
Yield: 2.6 %

Procedure:
A mixture of 5.0 g (21.4 mM) of the phenyl carbamate 8 and 1.2 g (10.7 mM) of 2-amino-3-methyl-pyridine in 25 ml of anhydrous DMF was heated at 55° for 3 hrs. and then cooled. The solid was collected via filtration and washed successively with cold DMF, ethyl acetate and ether. Recrystallization from ethanol and a final wash with water gave 0.07 g of the above urea as a pale yellow solid, m.p. 219°-221° C. (dec.).
Reaction SMILES: COC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)[C@H](CC=C)CC=2C=1.CN1[C@@H](C)[C@@H](C2C=CC=CC=2)N(C(=O)[C@@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCCCC=C)C1=O.[CH3:65][N:66]1[C@@H:70]([CH3:71])[C@@H:69]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[N:68]([C:78](=[O:125])[C@@H:79]([CH2:110][CH2:111][C:112]([F:124])([F:123])[C:113]([F:122])([F:121])[C:114]([F:120])([F:119])[C:115]([F:118])([F:117])[F:116])[CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85]/[CH:86]=[CH:87]/[CH2:88][C@@H:89]2[CH2:106][C:105]3[CH:104]=[C:103]([O:107][CH3:108])[CH:102]=[CH:101][C:100]=3[C@@H:99]3[C@@H:90]2[C@H:91]2[C@@:95]([CH2:97][CH2:98]3)([CH3:96])[C@@H:94]([OH:109])[CH2:93][CH2:92]2)[C:67]1=[O:126]>ClCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:65][N:66]1[C@@H:70]([CH3:71])[C@@H:69]([C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[N:68]([C:78](=[O:125])[C@@H:79]([CH2:110][CH2:111][C:112]([F:123])([F:124])[C:113]([F:122])([F:121])[C:114]([F:120])([F:119])[C:115]([F:118])([F:117])[F:116])[CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85]/[CH:86]=[CH:87]\[CH2:88][C@@H:89]2[CH2:106][C:105]3[CH:104]=[C:103]([O:107][CH3:108])[CH:102]=[CH:101][C:100]=3[C@@H:99]3[C@@H:90]2[C@H:91]2[C@@:95]([CH2:97][CH2:98]3)([CH3:96])[C@@H:94]([OH:109])[CH2:93][CH2:92]2)[C:67]1=[O:126]
Reactant: COc1ccc2c(c1)C[C@@H](C/C=C/CCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: C=CCCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C[C@@H](C/C=C\CCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Yield: 57 %

Procedure:
3-Methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol (377 mg, 1.16 mmol) and (4S,5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoyl]-5-phenylimidazolidin-2-one (1.36 g, 2.31 mmol) were dissolved in anhydrous dichloromethane (12 ml) at room temperature under nitrogen atmosphere. To this solution, benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (47.5 mg, 5.78×10−2 mmol) was added, and the resulting mixture was heated under reflux for 5 hours under nitrogen atmosphere. After cooling, the reaction mixture was filtered through an alumina pad. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel flash chromatography (Kanto Kagaku, silica gel 60 (spherical, neutral), 40–100 μm, eluent: ethyl acetate/n-hexane=1/1) to give a mixture of (4S,5R)-3,4-dimethyl-1-[(2R,9E)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl]-5-phenylimidazolidin-2-one and (4S,5R)-3,4-dimethyl-1-[(2R,9Z)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl]-5-phenylimidazolidin-2-one (579 mg, Yield 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:19])[F:20]
Reactant: CCOC(=O)c1ccc(-c2ccc(F)c(C(F)(F)F)c2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(F)c(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
Ethyl 5-[4-fluoro-3-(trifluoromethyl)phenyl]furan-2-carboxylate (136 mg, 0.45 mmol.) and LiOH (25 mg, 0.59 mmol) were diluted with THF/H2O=1:1 (3 mL), and then stirred for 1 hrs at room temperature. The mixture was acidified with 1N HCl, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield the crude title compound as a white solid (91 mg, 73%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][C:18]([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][CH:11]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][C:18]([C:23]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:24])=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2ccc(C(N)=O)c3[nH]c4cc(C(=O)N5CCN(C)CC5)ccc4c23)c1F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc(O)c4F)c23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A solution of 4-(2-fluoro-3-methoxyphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-137, 3.6 g, 7.82 mmol) in DCM (42 mL) was stirred at 0° C. and treated with boron tribromide (1 M in DCM, 94 mL, 94 mmol) and the mixture was stirred at rt overnight. The mixture was cooled again to 0° C. and treated slowly with methanol. The mixture was concentrated and purified by column chromatography on neutral alumina (eluting with 90:10 EtOAc-methanol) to provide 4-(2-fluoro-3-hydroxyphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a light colored solid (2.0 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.08 (s, 1H), 8.25 (br. s., 1H), 8.05 (d, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.59 (br. s., 1H), 7.17 (m, 3H), 7.11 (d, J=7.6 Hz, 1H), 6.99 (dd, J=8.0, 1.2 Hz, 1H), 6.91 (t, J=7.2 Hz, 1H), 3.51 (br. s., 2H), 3.34 (m, 5H), 2.34 (br. s., 4H). Mass spectrum m/z 447.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([C:4]2[N:3]=[C:2]([NH:33][C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[C:7]([C:8]#[N:9])=[CH:6][N:5]=2)=[N:11]1
Reactant: Nc1ccncc1
Reactant: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1

Procedure:
73 mg of 4-chloro-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidine-5-carbonitrile (1-14-1, 0.201 mmol, 1. eq.), 22.66 mg of pyridin-4-amine (0.241 mmol, 1.2 eq.), 42 μl of N-ethyl-N-(propan-2-yl)propan-2-amine (0.241 mmol, 1.2 eq.) and 1 ml of N,N-dimethylformamide were stirred at room temperature for 24 hours. The reaction mixture was partitioned between half-saturated aqueous sodium hydrogen carbonate solution and dichloromethane/isopropanol 4:1. The aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative HPLC to yield 24.4 mg (0.06 mmol, 28.9%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].FC1C=CC(N)=C(OC)C=1.[N+](C1C=CC=CC=1)([O-])=O>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([C:14]2[CH:13]=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[C:10]([CH3:9])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Agent: COc1cc(F)ccc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc(-c2ccc(F)cc2)ccc1[N+](=O)[O-]

Procedure:
When 4-fluoroaniline and 2-methyl-nitrobenzene are used in the above example in place of 4-fluoro-2-methoxyaniline and nitrobenzene there is obtained 4'-fluoro-3-methyl-4-nitrobiphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[C@@H:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)[C@@H](C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Temperature: -78 °C

Procedure:
1.95 of the ketone thus obtained was dissolved in 62 ml of tetrahydrofuran, and 7.0 ml of a 1M tetrahydrofuran solution of lithium tri-sec-butyl borohydride was added under cooling to -78° C. with stirring, followed by stirring at the same temperature for 30 minutes. To the reaction solution, 20 ml of a 0.5N sodium hydroxide aqueous solution was added, and then 10 ml of a 30% hydrogen peroxide aqueous solution was dropwise added thereto. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted by an addition of water and ethyl acetate, followed by conventional post-treatment. Then, purification was conducted by medium pressure liquid chromatography (hexane/ethyl acetate=5/1) to obtain 1.91 g of (2S*,3S*,5E)-3-(4-chlorophenyl)-6-(2-naphthyl)-5-hexen-2-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]([F:16])([F:15])[C:12](O)=O>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:12]([C:11]([F:16])([F:15])[F:10])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc(Br)cnc1N
Agent: Cl
Product: FC(F)(F)c1nc2ncc(Br)cc2[nH]1

Procedure:
A solution of 5-bromopyridine-2,3-diamine (100 mg, 0.53 mmol) in trifluoroacetic acid (20 mL) and hydrochloric acid (4 mL) was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and dissolved in water (100 ml), adjusted to pH 8 with sodium carbonate and extracted with ethyl acetate (3×80 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to produce 6-bromo-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine as a brown solid (200 mg, crude). To a solution of (4-chlorophenyl)boronic acid (117 mg, 0.75 mmol) in water (5 mL) and dioxane (15 mL) was added 6-bromo-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine (100 mg, crude), Pd(PPh3)4 (43.4 mg, 0.04 mmol) and sodium carbonate (119.5 mg, 1.13 mmol). The resulting solution was stirred overnight at 100° C. with an inert atmosphere of nitrogen and then concentrated under vacuum. The residue was dissolved in water (50 mL), extracted with ethyl acetate (4×50 mL), the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (60 mg) was purified by Prep-HPLC to produce 6-(4-chlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. TFA salt as a white solid (30 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].N1C2C(=CC=CC=2)[C:15](CC(O)=O)=[CH:14]1>>[C:3]1([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Product: CCOC(=O)Cc1ccccc1

Procedure:
I-3. Other helper inducers we have so for discovered such as 2,4-dichlorophenyl acetic acid, and indole-3-acetic acid were obtained from Sigma Chemical Company.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[C:25](F)[CH:24]=[C:23]([F:31])[C:22]=1[F:32].C(OCC)(=O)C>C1COCC1.CCCCCC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][C:25]1[C:26]([N+:27]([O-:29])=[O:28])=[C:21]([C:22]([F:32])=[C:23]([F:31])[CH:24]=1)[NH:20][C:14]1[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:13]=1[F:12])[CH3:2]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CCOC(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-])OCC
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
2,2-Diethoxy-ethanol (0.209 g, 1.2135 mmol) was added to a cooled suspension of NaH (0.034 g, 1.456 mmol) in THF (5 mL) at 0° C. and the resulting mixture was stirred for 30 minutes at 20-40° C. 2-Fluoro-4-iodo-phenyl-(2,3,5-trifluoro-6-nitro-phenyl)-amine (0.5 g, 1.2135 mmol) in THF (10 mL) was added slowly to the reaction mass at 0° C. and stirring was continued for a further 15 minutes. The reaction mass was stirred overnight at room temperature. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 0.3 g of the product (47% yield). 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, 1H), 7.35 (d, 1H), 6.90 (bs, 1H), 6.58-6.68 (m, 2H), 4.58 (t, 1H), 4.15 (d, 2H), 3.51-3.80 (m, 4H), 1.22 (t, 6H).
Reaction SMILES: [N:1]([C:4]1([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH2:12]([O:19][CH2:20][CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N:1]([C:4]1([C:9]([NH:22][CH2:21][CH2:20][O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1(C(=O)Cl)CCCC1
Reactant: NCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1(C(=O)NCCOCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Azidocyclopentan-1-carbonylchloride (16.8 g) was added to a mixture of 2-benzyloxyethylamine (14.7 g), K2CO3 (16.6 g) and acetone at 0° C. After stirring at room temperature for 2 h the mixture was filtered, concentrated in vacuo and after addition water (100 ml) extracted with diethyl ether (2×100 ml).The combined organic phases were washed with brine and dried (Na2SO4). Evaporation of the solvents gave the crude 12a as an oil: 22.3 g.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:35][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cncnc4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cncnc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-5-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1 N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield the desired product. 1H NMR (400 MHz, CDCl3) δ9.23 (s, 1 H), 9.20 (s, 2 H), 8.16 (d, 2 H), 7.65 (d, 2 H), 6.86 (d, 2 H), 6.76 (d, 2 H), 4.20 (t, 2 H), 3.00 (t, 2 H), 2.39 (s, 3 H), 1.48 (s, 6 H); MS (EI) 460.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([Cu])#[N:13].O>CN(C)C=O.Cl.[Fe](Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: N#C[Cu]
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)CCC2=O

Procedure:
9.5 g of 5-bromo-1-indanone and 4.93 g of CuCN are suspended in 10 ml of dimethylformamide and boiled under reflux for 4 hours. A solution of 18 g of iron(II) chloride in 5 ml of concentrated hydrochloric acid with 30 ml of water are added dropwise to the cooled, dark-brown viscous suspension while stirring, and the mixture is then stirred at 70° C. for 30 minutes. The reaction mixture is extracted by shaking three times with 50 ml of toluene, and the combined organic phases are extracted by shaking with 50 ml of 2N hydrochloric acid and 50 ml of 2N sodium hydroxide solution and then washed with water until neutral. The toluene extract is dried over magnesium sulfate and concentrated in vacuo, and the residue is recrystallized from n-heptane. 1-oxoindane-5-carbonitrile is obtained with a melting point of 123-125° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20]>CN(C)C=O.C(OCC)C>[CH:4]([C:3]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:2]=1[O:1][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])=[O:5]
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)OCCOc1ccc(C)cc1C=O
Temperature: 100 °C
Yield: 100 %

Procedure:
To a solution of 2-hydroxy-5-methyl-benzaldehyde (2.4 g, 18 mmol) (Aldrich) in N,N-dimethylformamide (30 mL) was added cesium carbonate (6 g, 18 mmol), potassium iodide (3 g, 18 mmol) and 2-bromoethyl acetate (7 g, 42 mmol), Aldrich). The reaction mixture was heated at 100° C. for 3 h. The mixture was cooled to room temperature and diluted with ethyl ether, washed with water, brine, separated, and concentrated. The residue was purified by chromatography (EtOAc:Hexanes=1:6) to give acetic acid 2-(2-formyl-4-methyl-phenoxy)-ethyl ester as a yellow oil (Yield 4 g, 100%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:23])([F:22])[C:16]1([C:19](O)=[O:20])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:19]([C:16]2([C:15]([F:23])([F:22])[F:14])[CH2:18][CH2:17]2)=[O:20])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: NCc1ccc(F)c([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1

Procedure:
The sub-title compound was prepared in accordance with the procedure in Example 72, step (c) using (4-fluoro-3-nitrophenyl)methylamine hydrochloride (3.0 g; 14.5 mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic acid (2.5 g; 16.0 mmol), HBTU (6.07 g; 16.0 mmol), TEA (5.88 g; 58.1 mmol) and DMF (50 mL). Yield: 3.8 g (85%).