Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:12]I.O>O1CCCC1>[CH3:12][O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)(C)C(=O)OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A solution of methyl 3-hydroxy-2,2-dimethylpropionate (25.0 g) in tetrahydrofuran (300 ml) was added dropwise to a suspension composed of a 60% oil suspension of sodium hydride (8.32 g) and tetrahydrofuran (100 ml) under ice cooling, and the mixture was stirred at 60° C. for 1 hour. Methyl iodide (53.7 g) was added to the reaction mixture, and the resultant mixture was stirred at room temperature for 2 hours. Water was carefully added to conduct extraction twice with methylene chloride. After the resultant organic layer was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resultant oil was distilled to obtain the title compound (12.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([C:15](OCC)=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(OCc3ccccc3)cc(CO)cn2c1C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
A solution of 1.2 g of 8-benzyloxy-6-ethoxycarbonyl-2,3-dimethylimidazo[1,2-a]pyridine in 20 ml of tetrahydrofuran is treated in small portions with 0.2 g of lithium aluminum hydride at room temperature stirred for one hour and treated successively with 0.2 ml of water, 0.2 ml of 6 molar sodium hydroxy solution and 0.6 ml of water. It is then extracted twice with methylene chloride (50 ml each), the combined organic phases are concentrated to dryness in vacuo and the residue is purified on silica (eluent: methylene chloride/methanol 13/1). 0.4 g of the title compound of melting point 213-5° C. (acetone) is obtained.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33](O)=[O:34])([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[CH3:49][C:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33]([NH:56][S:53]([C:50]5([CH3:49])[CH2:52][CH2:51]5)(=[O:55])=[O:54])=[O:34])([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 6.9 %

Procedure:
Compound 3j (120 mg, 0.233 mmol) was dissolved in DCM (10 ml). EDAC (54 mg, 0.28 mmol) was added and the reaction mixture was stirred at RT for 2.5 h. Methyl cyclopropanesulfonic amide (35 mg, 0.256 mmol) and DBU (73 μl, 0.489 mmol) were added and the reaction mixture was stirred at RT over night. 5% Citric acid was added and the organic layer was separated and washed with brine, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound (10.2 mg, 21%), MS (M+H)+632.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:24]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=1)#[CH:25].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[Cu]I.O>[NH2:1][C:2]1[C:3]2[C:10]([C:25]#[C:24][C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)=[CH:9][N:8]([C@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#Cc1cc(OC)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(N)ncnc32)C1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
PdCl2(dppf)2CH2Cl2 (122 mg) was added to a mixture of (S)-tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (660 mg) obtained in Step 2 above, 1-ethynyl-3,5-dimethoxybenzene (374 mg), copper (I) iodide (44 mg), and triethylamine (2.0 ml) in THF (15 ml). After nitrogen purging, the resulting mixture was stirred at 80° C. for 3.5 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After washing with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (714 mg). Physical properties: m/z [M+H]+ 464.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:28](=[O:30])[CH3:29])=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:24])[CH3:25]
Reactant: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(O)cc3)n2C)ccc1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
2.1 g (5 mmoles) of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-hydroxyphenylimino)-3-methyl-4-thiazoline (Example 2) are suspended in 25 ml of acetic anhydride and the yellow solution which results on warming, is stirred for 1 hour at 120° C. After distilling off the acetic anhydride in vacuo, the solid residue is recrystallized from isopropanol. Colorless crystals of m.p. 173°-174° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:17]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:19])=[O:18].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[CH:7]([NH:14][S:17]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)C(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a stirred solution of tert-butyl-2-amino-2-phenylacetate (1.34 g, 6.45 mmol) and methyl 3-(chlorosulfonyl)benzoate (1.53 g, 6.51 mmol) in tetrahydrofuran (15 mL) was added triethylamine (0.90 mL, 6.45 mmol) in one portion at ambient temperature. The reaction mixture was stirred for 30 minutes, after which time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (30 mL) and 10% citric acid solution (10 mL). The resulting organic phases were dried over magnesium sulfate and concentrated under reduced pressure to yield a crude solid. The solid was triturated in diethyl ether (5 mL) and cold methanol (5 mL) to yield the title compound as a white solid (1.13 g, 43%).
Reaction SMILES: [F:1][C:2]([F:30])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C.C1COCC1.Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:30])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:22]=[CH:21][CH:20]=[C:17]([C:18]3[NH:37][N:36]=[N:35][N:19]=3)[CH:16]=2)[CH2:23][CH:24]([OH:29])[C:25]([F:27])([F:28])[F:26])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(-c2nnn[nH]2)c1)C(F)(F)F
Temperature: 105 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile (76 mg, 0.17 mmol) in 2 mL of toluene was added trimethyltin azide (41 mg, 0.20 mmol). The reaction mixture was heated to 105° C. and stirred overnight. TLC showed starting material to still be present so additional trimethyltin azide (41 mg, 0.20 mmol) was added. The reaction mixture was stirred overnight at 105° C., cooled to room temperature, then THF (800 μL) and concentrated HCl (500 μL) were added. HPLC analysis showed 2 peaks after 5 hours, so additional concentrated HCl (200 μL) was added. After stirring overnight, HPLC analysis showed the reaction to be complete. The mixture was filtered through a celite plug and evaporated in vacuo. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 27.2 mg (33%) of the desired tetrazole product as an oil. HRMS calcd. for C19H16F7N5O2: 480.1270 [M+H]+, found: 480.1252. 1H NMR (CDCl3) δ3.66-3.99 (m, 2H), 4.45-4.75 (m, 3H), 5.80 (dt, 1H), 6.49-6.70 (m, 1H), 6.95 (s, 1H), 6.97-7.06 (m, 3H), 7.18-7.28 (m, 3H), 7.34 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][CH:14]1[CH2:18][CH2:17][CH:16]([CH3:19])[NH:15]1>C(O)C>[CH3:13][CH:14]1[CH2:18][CH2:17][CH:16]([CH3:19])[N:15]1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC1CCC(C)N1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(N2C(C)CCC2C)n1

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 40 ml of ethanol and 4.2 g (0.042 mol) of 2,5-dimethylpyrrolidine were placed in a fully equipped round-bottomed flask.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[C:13]([F:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of (5-bromo-3-fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester (600 mg, 2.06 mmol) in dry DMF (20 mL), NaH (130 mg, 3.08 mmol) was added at 0° C. The solution was stirred vigorously for 10 minutes at 0° C. and MeI (180 μL, 2.88 mmol) was added. After 30 minutes, the reaction mixture was quenched with NH4Cl (saturated aqueous solution) and the product was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by Biotage using 3-15% EtOAc in hexane to afford title compound (470 mg) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J=1.95 Hz, 1 H) 7.52 (dd, J=8.59, 1.95 Hz, 1 H) 3.22 (s, 3 H) 1.37 (s, 9 H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18]O)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[O:8][CH3:9].N1C=CC=CC=1.S(Cl)([Cl:28])=O>ClCCl>[Cl:28][CH2:18][C:4]1[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1c(F)cc(CO)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(F)cc(CCl)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of {3-fluoro-4-(methyloxy)-5-[(phenylmethyl)oxy]phenyl}methanol (2.69 g, 10.26 mmol.) in dichloromethane (40 mL) was cooled to 0° C. followed by addition of pyridine (913 uL, 11.3 mmol.) then thionyl chloride (750 uL, 10.3 mmol.). The mixture was then allowed to warm to room temperature followed by addition of a second aliquot of pyridine (400 uL). After 5 minutes the organic solution was washed once with 0.1M aqueous hydrochloric acid then dried over anhydrous magnesium sulfate. Filtration and concentration afforded 5-(chloromethyl)-1-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene (2.88 g, 100% yield) as a clear oil that was used without further purification. GCMS for C15H14O2FCl: 280 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25](OCC)=[O:26])[N:24]=2)[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]([NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][C:11]([F:13])([F:12])[F:14])[CH:4]=3)=[O:26])[N:24]=2)[CH:21]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1ccc(F)c(OC(F)(F)F)c1
Product: O=C(NCc1ccc(F)c(OC(F)(F)F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-fluoro-3-(trifluoromethoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:37]#[N:38])=[CH:7][N:6]=1)([CH3:3])[CH3:2].O.[Li+].[OH-]>C1COCC1>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([C:37]#[N:38])=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(Nc4ccccc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Nc1ncc(C#N)c(-c2c[nH]c3ncc(Nc4ccccc4)cc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
2-(isopropylamino)-4-(5-(phenylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (0.083 g, 0.158 mmol) was stirred in THF (7 mL) and water (1.5 mL) and treated with LiOH.H20 (0.066 g, 1.60 mmol, 10.0 Eq) and allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography (50% EtOAc/Petroleum ether) to yield the product as a yellow solid (29 mg, 50%)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH:15]([OH:17])[CH3:16])=[C:13]([CH3:18])[N:12]=[C:11]2[S:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])=[CH:6][CH:5]=1.Br.Br[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH:15]([O:17][CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[CH3:16])=[C:13]([CH3:18])[N:12]=[C:11]2[S:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])=[CH:6][CH:5]=1
Reactant: Cc1nc(SCc2c(F)ccc(F)c2F)n(-c2ccc(F)cc2)c1C(C)O
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(SCc2c(F)ccc(F)c2F)n(-c2ccc(F)cc2)c1C(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 60 mg, 1.44 mmol) was added to a solution of 1-(1-(4-fluorophenyl)-4-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazol-5-yl)ethanol (62) (190 mg, 0.48 mmol) in THF (5 mL) and the reaction was allowed to stir at room temperature for 20 min. 4-(bromomethyl)pyridine hydrobromide (146 mg, 0.576 mmol) was added to the reaction mixture and heated to 70° C. overnight. The reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 4-((1-(1-(4-fluorophenyl)-4-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazol-5-yl)ethoxy)methyl)pyridine (628). 1H NMR (400 MHz, CDCl3) δ: 8.56 (d, J=6.0, 2H), 7.20-7.17 (m, 4H), 7.04-6.96 (m, 3H), 6.74-6.68 (m, 1H), 5.31-5.15 (m, 2H), 4.63 (q, J=6.4, 1H), 4.48 (d, J=13.5, 1H), 4.32 (d, J=13.5, 1H), 2.19 (s, 3H), 1.45 (d, J=6.4, 3H). LC-MS ESI m/z; found 488.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH2:14][CH2:13][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: N#Cc1c(Cl)cccc1-n1cccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1c(Cl)cccc1-n1cccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A solution of 1-(3′chloro-2′-cyanophenyl)pyrrole (10 g) in diethyl ether solution was added dropwise to a solution of 1M lithium aluminium hydride in ether solution (100 ml) under nitrogen gas. After addition was complete, the reaction mixture was refluxed for 2 h. and then allowed to stir at room temperature overnight (18 h). The mixture was subsequently quenched with water (4 ml), 2N NaOH (8 ml) and water (16 ml). Stirring was continued for a further 1 h after addition. The crystalline salts were filtered and the filtrate dried over anhydrous magnesium sulphate. After filtering, the ether filtrate was evaporated in vacuo to give the title compound (9.4 g) as a colourless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(CCCO)c1cccc[n+]1[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCOS(C)(=O)=O)c1cccc[n+]1[O-]
Yield: 63.6 %

Procedure:
Methanesulfonyl chloride (0.17 mL, 2.20 mmole) was added dropwise to a solution of 2-[N-(3-hydroxy-1-propyl)-N-(tert-butoxycarbonyl)amino]pyridine-N-oxide (0.50 g, 1.86 mmole) and pyridine (0.23 mL, 2.84 mmole) in CHCl3 (5 mL, dried over K2CO3) at 0° C. When complete by TLC, the reaction was diluted with CHCl3, washed with ice water, dried (Na2SO4), and concentrated. Silica gel chromatography (10% MeOH/CHCl3) gave the title compound (0.41 g, 64%) as a colorless oil: 1H NMR (250 MHz, CDCl3) δ8.25 (dd, J=6.0, 1.9 Hz, 1 H), 7.25 (m, 4 H), 4.35 (t, J=6.2 Hz, 2 H), 3.75 (t, J=6.6 Hz, 2 H), 3.00 (s, 3 H), 2.00 (m, 2 H), 1.40 (s, 9 H). Unchanged 2-[N-(3-hydroxy-1-propyl)-N-(tert-butoxycarbonyl)amino]pyridine-N-oxide (0.18 g, 36%) could also be recovered from the chromatographic purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:14]([O:21][CH2:22][CH2:23][OH:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CN1CCOCC1>C(Cl)Cl>[Si:14]([O:21][CH2:22][CH2:23][O:24][C:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=1)=[O:10])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 604 mg (3.00 mmol) sample of p-nitrophenoxycarbonylchloride in 3 mL of methylene chloride was added to a solution of 0.528 g (3.00 mmol) of 2-(t-butyldimethylsilyloxy)ethanol and 0.330 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The solution was stirred for 2 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.453 g of the title compound, which was taken directly to the next step.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([S:20][CH3:19])[CH:22]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: CSc1cccc(O)c1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)c1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 3-methylsulfanyl-phenol (77 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (50 mg) as pale green solid.
Reaction SMILES: [C:1]([CH:8]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([OH:29])=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:30][CH3:31])=[CH:12][C:11]=1[CH2:32][CH2:33][CH3:34])([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:1]([CH:8]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([OH:29])=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:30][CH3:31])=[CH:12][C:11]=1[CH2:32][CH2:33][CH3:34])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)O)nc32)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)O)nc32)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To a solution of 3-[4-(1-carbo-t-butoxy-1-phenylmethoxy)-3propylphenylmethyl]-5-carboxy-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (47 mg, 0.087 mmol) in CHCl3 (3 mL) was added TFA (0.5 mL) at -20° C. The solution was warmed to rt and was stirred at rt for 12 hours. After evaporation of the solvent the crude mixture was purified by flash chromatography eluted with CHCl3 /MeOH/AcOH (90:5:5) to give 31 mg of the title compound as a white solid.