Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]OS(C)(=O)=O)=[CH:32][CH:31]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH2:37][CH2:36][C:33]1[CH:32]=[CH:31][C:30]([O:29][S:26]([CH3:25])(=[O:27])=[O:28])=[CH:35][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cc2ccccc2)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(Cc2ccccc2)c1)OCC
Yield: 36.1 %

Procedure:
Ethyl 3-(3-benzyl-4-hydroxyphenyl)-2-ethoxypropanoate (0.50 g, 3.73 mmole) and 4-{2-[(methylsulfonyl)oxy]ethyl}phenyl methanesulfonate (2.20 g, 7.46 mmole) were dissolved in 2-butanone (20 ml). Polyethyleneglycol 400 (0.20 g) and anhydrous potassium carbonate (0.78 g, 5.59 mmole) were added the mixture. After stirring at reflux for 16 hours it was checked using HPLC whether all the starting material was consumed. The mixture was washed with water dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 10 μm, 50×500 mm) using acetonitrile (60-80%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.71 g (36% yield) of the desired product
Reaction SMILES: [S:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[S:4][CH2:3][CH2:2]1.[H-].[Na+].[C:14](=O)([O:17]C)[O:15][CH3:16]>C1COCC1>[CH3:16][O:15][C:14]([C:9]1[CH2:10][C:5]2([CH2:6][CH2:7][C:8]=1[OH:11])[S:4][CH2:3][CH2:2][S:1]2)=[O:17]
Reactant: COC(=O)OC
Reactant: O=C1CCC2(CC1)SCCS2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CCC2(C1)SCCS2
Temperature: 25 °C

Procedure:
To 1,4-dithia-spiro[4.5]decan-8-one (2.35 g, 12.5 mmoL, 1.0 eq), in THF (10 mL) at 0° C. under nitrogen was added NaH (60%, 2.0 g, 50 mmoL, 4.0 eq) slowly. After gas releasing was completed, dimethy carbonate (11.3 g, 125 mmoL, 10.0 eq) was added via syringe. The reaction mixture was warmed to room temperature and further heated at 50° C. for 2 hours. The reaction was then cooled down to room temperature and quenched with saturated ammonia chloride solution. The solvent was removed in vacuo and the residue was partitioned between ethyl ether and water. The aqueous layer was extracted with ethyl ether twice. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a colorless oil. The crude material was then purified by column chromatography using 5:1 hexanes: ethyl acetate to give the title compound as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:11]1[N:12]=[CH:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[N:17]([CH3:26])[CH2:16][C:15]=12)=O)[C:4]([O:6][CH3:7])=[O:5].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1.ClCCl>[CH3:26][N:17]1[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:14]2[CH:13]=[N:12][C:11]([C:9]3[O:1][CH2:2][C@@H:3]([C:4]([O:6][CH3:7])=[O:5])[N:8]=3)=[C:15]2[CH2:16]1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2ccccc2-3)=N1
Yield: 46.3 %

Procedure:
A solution of 10.0 g (0.0279 mol) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-ylcarbonylamino)-propionate in 500 ml of tetrahydrofuran was treated while gassing with argon with 7.25 g (0.0304 mol) of methoxycarbonylsulphamoyl-triethylammonium hydroxide internal salt (Burgess reagent) according to the method described in Tert. Letters 1992, 33, 907. The mixture was boiled at reflux for 1 hr. and completely freed from the solvents. The residue was dissolved in dichloromethane and chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent. There were obtained 4.4 g (46%) of methyl (S)-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate as a white solid. An analytical sample was recrystallized from ethanol/diethyl ether and gave white crystals; m.p. 190°-192°. [α]D20 =+45.4° (CHCl3, c=1%).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.COCCOC.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>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:10]3[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1nc2cccc(Br)c2s1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2cccc3nc(NC(C)=O)sc23)cc1
Temperature: 85 °C
Reaction time: 0.83 h

Procedure:
N-(7-Bromobenzo[d]thiazol-2-yl)acetamide (56.5 mg, 0.208 mmol), 4-methoxybenzeneboronic acid (47.8 mg, 0.315 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (30.7 mg, 43.7 μmol), and sodium carbonate (0.31 mL, 2 M, 0.62 mmol) were suspended in EtOH (0.25 mL) and 1,2-dimethoxyethane (0.9 mL). The flask was fit with a reflux condensor and placed in a preheated oil bath (85° C.) and stirred under nitrogen for 50 minutes. The reaction was cooled to RT, and filtered through a pad of Celite® (diatomaceous earth). This pad was washed with DCM and MeOH, and the filtrate was concentrated and filtered through a silica gel pad with 10:1 DCM/MeOH. The filtrate was concentrated and purified on HPLC (10-95% MeCN/water with 0.1% TFA over 30 minutes) to provide N-(7-(4-methoxyphenyl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 299 (MH+). Calculated exact mass for C16H14N2O2S: 298. 1H NMR (400 MHz, DMSO-d6): 12.34 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.5 Hz, 5H), 7.51 (t, J=7.8 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 3.81 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[C:29]=1Cl)[CH:25]=[O:26].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:29]3[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][C:22]=3[C:21]([F:20])([F:35])[F:36])[CH:3]=2)[NH:7][CH:6]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Reactant: CC(C)c1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(C=O)cc3C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
12.8 g (70.27 mmol) of 5-hydroxy-3-isopropyl-indole are dissolved in 275.8 ml of DMSO, 10.68 g (77.3 mmol) of potassium carbonate are introduced in solid form, the mixture is stirred for 10 minutes at room temperature and afterwards 19.43 g (70.27 mmol) of 3,5-bistrifluoromethyl-4-chlorobenzaldehyde are introduced in portions. After stirring at 50° C. for 3 hours the batch is poured onto a mixture of 400 ml of ethyl acetate and 250 ml of saturated ammonium chloride solution. After phase separation, the aqueous phase is extracted again with ethyl acetate, and the combined organic phases are washed twice with sodium chloride solution and dried over sodium sulphate. After removing the drying agent and distilling off the solvent the crude product is chromatographed on silica gel 60 (Merck 0.040-0.063 mm) using toluene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[C:27]1[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:27]2[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
1-t-butoxycarbonyl-4-hydroxypiperidine (408 mg, 2.03 mmol) and cesium carbonate (764 mg, 2.34 mmol) were added to a DMF solution (10 ml) of 2-chloro-5-bromopyrimidine (300 mg, 1.56 mmol), and stirred at room temperature for 14 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane:ethyl acetate=10:1) to obtain the entitled compound (268 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]SC3C([N+]([O-])=O)=CC=CN=3)[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[CH2:59][C:60]([C:62]1[CH:63]=[CH:64][C:65]2[O:69][CH2:68][CH2:67][C:66]=2[CH:70]=1)=[O:61].CCN(CC)CC>CC(C)=O.O>[O:69]1[C:65]2[CH:64]=[CH:63][C:62]([C:60](=[O:61])[CH2:59][S:13][C@H:10]3[C:11](=[O:12])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:9]3[C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:37][CH:38]=3)=[CH:70][C:66]=2[CH2:67][CH2:68]1
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(CCl)c1ccc2c(c1)CCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)CCO4)C(=O)N2c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of tert-butyl (4-{(2R,3R)-1-(4-fluorophenyl)-3-[(3-nitropyridin-2-yl)dithio]-4-oxoazetidin-2-yl}phenoxy)acetate (50.0 mg, 0.090 mmol) in acetone (6 ml) and water (0.8 ml) was added triphenylphosphine (33.3 mg, 0.013 mmol). The reaction mixture was stirred for 15 minutes. The solvent was removed under reduced pressure and the crude thiol was dissolved in DCM (12 ml). Et3N, (30 pd, 0.22 mmol) was added. After 5 minutes, 2-chloro-1-(2,3-dihydro-1-benzofuran-5-yl)ethanone (37.2 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight. Additional triphenylphosphine (11.6 mg, 0.04 mmol), Et3N (10 μl, 1, 0.07 mmol) and 2-chloro-1-(2,3-dihydro-1-benzofuran-5-yl)ethanone (7.2 mg, 0.04 mmol) were added and the reaction mixture was stirred for 1 hour. The formation of the tert-butyl ester of the title compound was confirmed. M/z: 564.24 (M+1) and 562.21 (MA). To the DCM solution of the previous reaction was added TFA (6 ml) and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was purified with preparative HPLC on a C8 column. A gradient from 20 to 70% ACN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was diluted with additional water and EtOAc. The water phase was acidified with KHSO4 (2M) to pH 2. The phases were separated and the organic phase was passed through a phase separator and concentrated. The oily residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 3.17 (t, 2H), 4.23 (ABq, 2H), 4.28 (d, 1H), 4.52 (b, 2H), 4.59 (t, 2H), 5.11 (d, 1H), 6.78-6.88 (m, 3H), 7.09-7.15 (m, 2H) 7.16-7.22 (m, 2H), 7.30 (d, 2H), 7.71-7.76 (m, 1H), 7.79 (s, 1H). M/z: 508.13 (M+1) and 506.22 (M−1).
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([F:13])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:12][C:11]1[C:2]2[O:7][CH2:6][CH2:5][O:4][C:3]=2[C:8]([F:13])=[CH:9][CH:10]=1
Reactant: OCCOc1c(F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(F)c2c1OCCO2

Procedure:
2-(2,3,6-Trifluorophenoxy) ethanol (48.8 g, 0.254 mole) and 24 g of anhydrous potassium carbonate in 800 ml of dimethylformamide was refluxed for 20 hours and then poured into water. This was extracted with ether, washed with water, and dried to give 5,8-difluoro-1,4-benzodioxane.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19]S(C)(=O)=C>CS(C)=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:19][CH:14]3[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=S(C)(C)=O
Reactant: COC(=O)/C=C/c1ccc(C2CCCCC2)cc1
Solvent: CS(C)=O
Product: COC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To a solution of (E)-methyl 3-(4-cyclohexylphenyl)acrylate (200 mg, 0.82 mmol) in DMSO (20 mL) was added freshly prepared Corey's reagent (92 mg, 0.98 mmol) at RT and stirred for 3 h. The reaction was quenched with cold water and then extracted with EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and then concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc/95% hexanes to afford methyl 2-(4-cyclohexylphenyl)cyclopropanecarboxylate (150 mg, 47%) as a solid.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[O:13][C:12]([CH2:14][O:15]C(=O)C)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]1([NH:7][CH2:8][C:9]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCc1ccc(CNc2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Nc1ccccc1
Product: OCc1ccc(CNc2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Then, the resulting mixture of acetic acid 5-phenylaminomethyl-furan-2-ylmethyl ester and aniline (2.91 g) as well as potassium carbonate (3.28 g, 23.7 mmol) were suspended in methanol (60 mL), and the solution was stirred overnight at room temperature. The reaction solution was evaporated in vacuo, water and ethyl acetate were added to the residue, the organic layer was partitioned, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (1.99 g, 9.79 mmol, 82%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4](OC)=[O:5].[NH2:27][C:28]([NH2:30])=[O:29]>C(O)C>[NH2:27][C:28]([NH:30][C:4](=[O:5])[C:3]1[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][C:10]([O:17][CH3:18])=[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:2]=1[OH:1])=[O:29]
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Reactant: NC(N)=O
Solvent: CCO
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)NC(N)=O)c1O
Temperature: 0 °C
Yield: 79 %

Procedure:
Dissolve compound 8 (1.0 g, 2.96 mmol) in anhydrous ethanol (20 ml), add in urea (0.27 g, 4.44 mmol), reflux to react for 12h, after completion of the reaction, pour the solution into ice water and extract three times with ethyl acetate, pool the organic layer, dry over anhydrous magnesium sulfate, filter and concentrate the solution, feed the solution to a silica gel column, evaporate the solvent in the eluent to obtain a white solid as the desired product (0.89 g, 80%). 1H NMR (400 MHz, DMSO-d6): 1.79 (s, 3H), 1.82 (s, 3H), 3.34 (d, J=7.6 Hz, 2H), 3.83 (s, 3H), 5.21 (t, J=7.6 Hz, 1H), 6.20 (s, 2H), 6.65 (s, 1H), 6.81 (d, J=16.0 Hz, 1H), 7.26 (d, J=16.0 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 9.89 (s, 1H), 11.77 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:15]2[CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][CH3:26])=[C:18]([C:27]([F:30])([F:29])[F:28])[CH:17]=3)[N:12]=[C:11]([C:31]#[N:32])[C:10]=2[N:9]=[CH:8]1.C(N(C(C)C)C(C)C)C>C1COCC1.C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([N:25]([CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:31]#[N:32])[C:10]3[N:9]=[CH:8][N:7]([CH3:6])[C:15]=3[CH:14]=2)=[CH:17][C:18]=1[C:27]([F:29])([F:30])[F:28])[CH3:26])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
At 0° C., 2-chloroacetyl chloride (127 mg) was added to a solution of 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (211 mg) and N-ethyl-N-isopropylpropan-2-amine (0.465 ml) dissolved in THF (5 ml). Reaction mixture was stirred at room temperature for 1 hour. Reaction mixture diluted with ethyl acetate, washed with sodium bicarbonate and water. Organic layer was dried over magnesium sulphate, solvent removed under vacuo to afford 2-chloro-N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-methylacetamide (205 mg). 1H NMR (CDCL3) δ: 8.22 (m, 2H), 8.08 (s, 1H), 7.87 (s, 1H), 7.13 (d, 1H), 4.32 (t, 2H), 4.13 (s, 2H), 3.99 (s, 3H), 3.88 (t, 2H), 3.29 (s, 3H). MS m/z 452.0 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]O)[CH:45]=1>O1CCCC1>[F:34][C:35]1[CH:42]=[C:41]([O:43][CH2:50][C:46]2[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=2)[CH:40]=[CH:39][C:36]=1[C:37]#[N:38]
Reactant: OCc1cccnc1
Reactant: N#Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cccnc2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
A solution of triphenylphosphine (20 g) in tetrahydrofuran (300 mL) cooled at 0° C. is treated dropwise during 5 minutes with diisopropyl azodicarboxylate (15 mL) and stirred for 15 minutes at 0° C. It is then treated, dropwise, with a solution of 2-fluoro-4-hydroxybenzonitrile (7 g) and 3-pyridylmethanol (7 g) in tetrahydrofuran (200 mL) during 2 hours, and stirring is continued at ambient temperature for 18 hours. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate (500 mL) and the solution is washed with hydrochloric acid (3×100 mL; 1 N) and the remaining organic layer is discarded. The combined acid washings are basified to pH 10 by treatment with solid sodium hydroxide and extracted with ethyl acetate (3×100 mL). This organic extract is dried over magnesium sulphate and concentrated in vacuo, and the residue is recrystallized from isopropyl ether, to give 2-fluoro-4-(3-pyridylmethoxy)benzonitrile (10 g), in the form of a white solid, m.p. 105-110° C.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[CH2:6][CH2:5]1>[Ni]>[F:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][CH:4]2[NH2:3])=[CH:8][CH:9]=1
Reactant: CON=C1CCc2ccc(F)cc21
Agent: [Ni]
Product: NC1CCc2ccc(F)cc21

Procedure:
The product of Example 135A and Raney/nickel were processed according to the method of Example 131C to provide the product. MS (ESI+) m/z 152 (M+H)+;
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: OB(O)c1cc2ccccc2o1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)cc1-c1cc2ccccc2o1
Reaction time: 5 h

Procedure:
A mixture of 2-bromo-4-fluorobenzonitrile (515 g, 25.65 mmol), benzofuran-2-ylboronic acid (5.0 g, 30.8 mmol), 1,2-dimethoxyethane (25 mL) and 2M Na2CO3 (40 mL) was heated to reflux before Pd2(dba)3 (100 mg) was added and heating was continued for 5 h. After cooling to r.t, EtOAc (20 mL) was added to dissolve the product. The mixture was filtered through celite, the organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was dissolved in minimum amount of CHCl3 and passed through Silica. Solvent was evaporated and the residue was first purified by crystallisation from a mixture CHCl3/PE (98/2). The filtrate was purified by Combiflash chromatography (40 g column, 13 g Silica, gradient of eluent from PE to PE/EtOac 9/1) to give the title compound as light yellow solid purified by rinsing with PE to give at the end a white solid (5.15 g). This solid had to be purified an ultimate time by drying under vacuum at 80° C. for O/N. Finally, pure expected compound was obtained as a off-white solid in 59% yield (3.6 g); mp 123-124° C.; 1H NMR (270 MHz, CDCl3) 87.13 (1H, td, J=2.5 and 7.3 Hz, ArH), 7.30 (1H, t, J=7.7 Hz, ArH), 7-40 (1H, t, J=77 Hz, ArH), 7.56 (1H, d, J=7.7 Hz, ArH), 7.69 (1H, d, J=73 Hz, ArH), 7.76-7.86 (3H, m, ArH); Anal. Calcd. for C15H8FNO: C, 75.94, H, 3.40, N, 5.90. Found: C, 75 70, H, 3.37, N, 5.97%.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(NC(C)=O)cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-ethyl-N-acetyl-aniline [3 g, Reference Example 33(a)] in acetic anhydride (8 mL) and acetic acid (4 mL), at −5° C., was treated dropwise with a mixture of acetic acid (1.75 mL) and concentrated nitric acid (1.22 mL). The mixture was warmed to 0° C., then stirred at 0° C. for 2 hours and then poured onto water. This mixture was evaporated and the resulting oil was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residual oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (2:5) to give 4-ethyl-2-nitro-N-acetyl-aniline (1.4 g) as an orange solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[Cl:17][C:18]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:7]1[CH2:8][CH2:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[CH2:6]1)=[O:21]
Reactant: c1cn2c(n1)CNCC2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2ccnc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazine (0.099 g, 0.804 mmol) was suspended in dichloromethane (DCM) (8 ml). Triethylamine (0.123 mL, 0.884 mmol) and 2-chloro-3-(trifluoromethyl)benzoyl chloride (0.195 g, 0.804 mmol) were added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, the residue dissolved in 1:1 DMSO/MeOH and purified by mass-directed automated preparative HPLC. Product fractions were concentrated in vacuo to yield an orange gum. This was partitioned between DCM (10 ml) and saturated aqueous sodium bicarbonate (4 ml) and the organic layer separated. This was concentrated in vacuo to yield 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.131 g, 0.397 mmol, 49.4% yield) as a yellow gum.