Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCC(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A solution of 3.5 g. of ethyl 4-(15-methylhexadecyl)aminobenzoate and 1.7 g. of 85% potassium hydroxide in 50 ml. of 95% ethanol is heated at reflux for 5 hours. The warm solution is diluted with 100 ml. water and adjusted to pH 5 with 37% hydrochloric acid. The precipitate is collected, dried, and crystallized from acetic acid to yield the title compound as an amorphous, cream-colored solid.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].C(OCl)(C)(C)C.[CH3:16][CH2:17][C:18](OCC)=[S:19].C(N(CC)CC)C.Cl>ClCCl.C(OCC)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[NH:7][C:18](=[S:19])[CH:17]2[CH3:16])#[N:2]
Reactant: CCOC(=S)CC
Reactant: N#Cc1ccc(N)cc1
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1C(=S)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-cyanoaniline (5.0 g, 42 mmol) in dry dichloromethane (100 mL) under N2 was cooled to about −78° C. To this stirred solution was added a solution of tert-butylhypochlorite (4.6 g, 42 mmol) in dry dichloromethane (10 mL) over 5 min. and the resulting solution stirred for 10 minutes. A solution of ethyl methylthioacetate (5.45 mL, 5.69 g, 42 mmol) in dry dichloromethane (10 mL) was than added dropwise and the mixture stirred for 1 hour. Triethylamine (5.9 mL, 4.28, 42 mmol) was added dropwise and the solution allowed to warm to room temperature over 1 hour. The reaction solution was washed with water (3×20 mL) and brine (1×20 mL), dried over anhydrous MgSO4 and the solvent evaporated under vacuum to leave an orange oil. This oil was dissolved in diethyl ether (100 mL) and 2N aqueous hydrochloric acid (5 mL) was added and the mixture stirred vigorously at room temperature for 18 hours. The resulting tan solid was collected by filtration and washed with diethyl ether and dried under vacuum to give 5-cyano-3-methylthiooxindole as a white solid, (6.4 g, 76%). 1H NMR (CDCl3) δ9.04 (br s, 1H) 7.64 (s, 1H), 7.57 (d, 1H, J=8.4 Hz), 6.99 (d, 1H, J=8.4 Hz), 4.28 (s, 1H), 2.04 (s, 3H). MS (−ve ES) 203 (100), (M−H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.OC1CCC(O)C1.FC1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])C=1>C(O)(C)(C)C>[Cl:28][C:22]1[CH:7]=[C:11]([O:10][CH:9]2[CH2:8][CH2:3][CH:2]([CH3:5])[CH2:1]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C1CCOC1
Agent: OC1CCC(O)C1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1CCC(Oc2ccc(C#N)c(Cl)c2)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A 1.0 M solution of potassium t-butoxide in t-butanol (0.3 mL) was added to a 8 mL vial fitted with a septa cap containing 0.3 mL of dry THF and 30 mg (0.3 mmoles) of 3-hydroxy cylcopentanol at 5° C. The mixture was stirred for 0.5 h at 5° C., after which time 0.3 mL of a 1.0 M THF solution of 4-fluoro-2-chloro-benzonitrile was added. The reaction was stirred at 5° C. for 3 h and then allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was cooled to 0° C., and quenched with 2 mL of water, diluted with 2 mL of methyl tert-butyl ether. The vial was shaken vigourously and the phases allowed to separate. The aqueous layer was removed with a pipette, and the organic layer washed with another 2 mL of water. The organic phase was dried (MgSO4), concentrated in vacuo, and the residue purified by reverse phase HPLC (Shimadzu) to give 36 mg (52%) of the title compound. GC/MS: 235 (M/Z for C13H14ClNO).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1.O>C1(C)C=CC=CC=1>[Cl:15][C:8]1[N:7]=[C:6]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of cyclopropylamine (1.25 g, 22.0 mmol) in toluene (11 mL) was added over 10 min to an ice-cold solution of 2,6-dichloro-3-nitropyridine (2.00 g, 10.4 mmol) in toluene (10 mL). The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Water (50 mL) was added to the mixture and the phases were separated. The organic layer was washed with brine (25 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 3:2) to give the title compound (1.97 g, 89% yield) as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>C(#N)C>[N:1]1[N:2]([CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[N:3]=[N:4][CH:5]=1
Reactant: ClCC1CO1
Reactant: c1nnn[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OC(CCl)Cn1ncnn1

Procedure:
6.905 g of tetrazole (100 mmol) and 1.75 ml of diisopropylethylamine (10 mmol) and 11.73 ml of epichlorohydrine (150 mmol) in anhydrous acetonitrile (30 ml) was stirred at 60° C. for 4 hours. The obtained solution was evaporated, dried on highvac and purified on a column of silica in chloroform-methanol 100:8. The first fraction provided pure 3-(2-H-tetrazol-2-yl)-2-hydroxy-1-chloropropane, 6.215 g (colorless oil, 38% Y), the second fraction yielded 9.208 g of pure 3-(1-H-tetrazol-1-yl)]-2-hydroxyl-1-chloropropane (sticky gum; 57%Y).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27](=O)[CH:28]([CH3:30])[CH3:29].C1(C)C=C[C:35]([S:38](O)(=[O:40])=[O:39])=CC=1.C([BH3-])#N.[Na+].Cl>ClCCl.O1CCOCC1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:38]([CH3:35])(=[O:40])=[O:39])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C

Procedure:
A solution of 0.60 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide, 0.166 ml isobutyraldehyde and a crystal of 4-toluenesulphonic acid in 10 ml of dichloromethane was stirred for 1 hour over 4 Å molecular sieves. The mixture was filtered and the solvent was evaporated and replaced with 10 ml of methanol. A few crystals of bromocresol green were added to give a yellow solution. To this was added 0.116 g of sodium cyanoborohydride in small batches. The yellow colour of the solution was maintained by the periodic addition of a 4M solution of hydrogen chloride in dioxane. The methanol was evaporated and the residue was partitioned between dichloromethane and 5% aqueous sodium hydrogen carbonate solution. The aqueous layer was washed twice with dichloromethane and then the combined organic layers were washed twice with 5% aqueous sodium hydrogen carbonate solution. The dichloromethane layer was dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (7:3) for the elution. There was obtained 0.312 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>CC#N.C(Cl)(Cl)Cl>[Br-:23].[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH2:27][O:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:29][CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(COCCBr)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(COCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)CC3)cc1
Product: [Br-]
Temperature: 60 °C
Yield: 73.5 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) was added to a solution of 4-{[(2-bromoethyl)oxy]methyl}benzonitrile (34 mg, 0.143 mmol) in 2:3 CH3CN/CHCl3 (3 mL), and the reaction was heated at 60° C. for 96 h. The reaction was concentrated, and the crude product was washed with EtOAc (3×1 mL). The product was dried under high vacuum to give the title compound (40 mg, 74%). LC/MS ESI RT 1.82 min M+453
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]2[C:5]=1[CH:6]([CH3:16])[NH:7][C:8](=[S:15])[NH:9]2>CC(C)=O.C(OCC)C>[IH:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]2[C:5]=1[CH:6]([CH3:16])[NH:7][C:8]([S:15][CH3:1])=[N:9]2
Reactant: CC1NC(=S)Nc2c(Cl)ccc(Cl)c21
Reactant: CI
Solvent: CCOCC
Solvent: CC(C)=O
Product: CSC1=Nc2c(Cl)ccc(Cl)c2C(C)N1
Product: I
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Methyl iodide (0.73 ml, 11.7 mmol) was added to a suspension of 5,8-dichloro-4-methyl-3,4-dihydro-1H-quinazoline-2-thione (0.96 g, 3.9 mmol) in acetone (12 ml), and the mixture was stirred at room temperature overnight. The reaction was diluted with diethyl ether, and the precipitated product (1.31 g, 86%) was isolated by filtration as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.O.[NH2:10][NH2:11]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cc(Br)ccn1
Temperature: 45 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
To a solution of 4-bromo-2-fluoropyridine (23.75 g, 135 mmol) in ethanol (120 mL) was added hydrazine monohydrate (65.5 mL, 1350 mmol). The mixture was stirred at 45° C. for 16 h then concentrated. The resulting solid was triturated with water, collected by filtration, rinsed with water, and dried under vacuum, to give the title compound (23.2 g) as a white solid. LCMS m/z=188.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 4.19 (s, 2H), 6.69 (dd, J=5.3, 1.8 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 7.69 (s, 1H), 7.84 (d, J=5.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:15](=[CH:21]O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH2:24].C1COCC1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][N:24]([CH3:23])[C:10](=[O:11])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)C=C(C(=CO)C(=O)OCC)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C)c(=O)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
A mixture of Example 41B (1.50 g, 4.62 mmol), 2M methylamine in THF (3.5 mL, 7.0 mmol), and acetic acid (1.5 mL) in ethanol (20 mL) was heated to reflux for 30 minutes, cooled to room temperature, and concentrated. The concentrate was dissolved in acetonitrile (15 mL), treated with K2CO3 (3.2 g, 23.0 mmol), stirred for 18 hours, and concentrated. The concentrate was dissolved in dichloromethane, washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 19:1 dichloromethane/acetone to provide 586 mg (41%) of the desired product. MS (DCI/NH3) m/z 292 (M+H)+; 1H NMR (CDCl3) δ 8.22 (s, 1H), 7.35 (m, 2H), 7.23 (m, 1H), 7.12 (m, 1H), 6.43 (s, 1H), 4.09 (q, 2H), 3.65 (s, 3H), 1.04 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[N:6][CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].BrCBr.CCOC(C)=O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:10][O:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)cnc1O
Agent: [K+]
Solvent: BrCBr
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Brc1cnc2c(c1)OCO2
Temperature: 90 °C

Procedure:
To a suspension of 5-Bromo-pyridine-2,3-diol (10.0 g, 52.63 mmol, commercially available, CAS 34206-49-0) in NMP (100 mL) was added K2CO3 (21.97 g, 158 mmol) and dibromo methane (10.97 g, 63.16 mmol). The reaction mixture was heated to 90° C. for 16 h. EtOAc was added and the salts were filtered off. Water was added, the phases were separated and the aq layer was extracted with more ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4 and concentrated under vacuo to get the crude compound. The crude compound was purified by silica gel chromatography (eluent 5% ethyl acetate in petrol ether). Yield of 6-Bromo-[1,3]dioxolo[4,5-b]pyridine 2.2 g (21%) pure by 1H NMR (400 MHz, DMSO) δ 7.71 (d, 1H, J=2 Hz), 7.55 (d, 1H, J=2 Hz), 6.20 (s, 2H). Mp 69-71 C.
Reaction SMILES: I[C:2]1[N:3](CCC)[CH:4]=[N:5][C:6]=1[CH:7]=[O:8].[C:12]1(C)[CH:17]=CC=C[CH:13]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:2]1[N:3]=[C:4]([CH2:13][CH2:12][CH3:17])[NH:5][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1ccco1
Reactant: CCCn1cnc(C=O)c1I
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(-c2ccco2)c(C=O)[nH]1
Reaction time: 0.08 h

Procedure:
A solution of 2.64 g (0.01 mol) of 4-iodo-3-n-propylimidazole-5-carboxaldehyde, 60 mL of toluene, and 0.33 g (0.00029 mol) of tetrakistriphenylphosphine palladium (0) was stirred at room temperature under nitrogen, while a solution of 2.34 g (0.0174 mol) of furan-2-ylboronic acid in 50 mL of ethanol was slowly added. The reaction was stirred for 5 minutes, after which 12 mL of 2M sodium carbonate was slowly added. After the addition was completed, the reaction was refluxed for 8 h and cooled. The reaction was filtered, the filtrate was evaporated under reduced pressure, and the resulting residue was dissolved in 300 mL of methylene chloride, washed twice with 100 mL of saturated sodium chloride solution, washed twice with 100 mL of distilled water, and washed twice with 300 mL of 10% HCl. The HCl layer was made basic with 50% sodium hydroxide until the pH=10. At this point, the basic water layer was extracted three times with 300 mL of methylene chloride, the methylene chloride layer was dried over sodium sulfate and evaporated under reduced pressure. Yield: 0.34 g (0.00156 mol, 5-carboxaldehyde. NMR (CDCl3) δ 10.14. (s,1H); 9.54 (s,1H); 7.00 (d,1H); 6.55 (m,1H); 2.79 (t,2H); 1.80 (m,2H); 1.02 (t,3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH2:6][C:5]2=[O:22].Br[Zn][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH2:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH2:6][C:5]2=[O:22])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)c2ccc(Br)cc21
Reactant: CC(C)(C)C[Zn]Br
Product: CC(C)(C)Cc1ccc2c(c1)C(=O)CCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzyl 6-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3.10 g) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.35 g) were combined in a round bottom flask. The mixture was put under high vacuum and purged with nitrogen. A 0.5 M solution of bromo(neopentyl)zinc (55 mL) prepared using the procedure of Negishi et al. Tet Lett. 1983, 24, 3823–3824, was added to the mixture and was stirred at room temperature for two days. The reaction had not gone to completion, so an additional 10 mL of bromo(neopentyl)zinc solution was added and the mixture was stirred for one additional day. The mixture was then partitioned between ethyl acetate and aqueous ammonium chloride, dried with magnesium sulfate, filtered, and concentrated. Silica gel chromatography using a 20% ethyl acetate in heptane solvent solution gave 2.17 g of the title compound. MS (ESI+) for C22H25NO3 m/z 353.17 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][CH2:32][CH2:33][OH:34]>>[OH:34][CH2:33][CH2:32][N:31]([CH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1)[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11]
Reactant: OCCNCc1ccccn1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1
Product: COc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ncccc2C)cn1

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([OH:24])=O)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(NC2CCCCC2)CCCCC1.[C:38]([O:42][C:43](=[O:48])[NH:44][CH2:45][CH2:46][NH2:47])([CH3:41])([CH3:40])[CH3:39].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@H:13]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C:22]([NH:47][CH2:46][CH2:45][NH:44][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:48])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.50 g (0.96 mmol) of 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)-L-alanine-N-cyclohexylcyclohexanamine (1:1) and 0.154 g (0.96 mmol) of tert-butyl(2-aminoethyl)carbamate are dissolved in 10 ml of dimethylformamide and 0.5 ml of triethylamine. Then, at 0° C. (ice bath), 0.314 g (1.64 mmol) of EDC and 0.043 g (0.32 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:25][O:26][CH2:27][CH3:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:48][C@H:49]2[O:51][CH2:50]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:48][C@@H:49]5[CH2:50][O:51]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:25][O:26][CH2:27][CH3:28])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CCOCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenol (0.21 g, 0.5 mmol, 1.0 eq.) and Cs2CO3 (0.49 g, 1.5 mmol, 3.0 eq.) in DMF (2 mL) was stirred and preheated to 80° C. The reaction mixture was then treated with a solution of (2S)-(+)-glycidyl tosylate (0.17 g, 0.75 mmol, 1.5 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for ˜30 min following completion of the addition. Analysis of the reaction by TLC and LC/MS showed that the starting phenol had been consumed and the desired alkylated-phenol was the major product. The reaction was then cooled and diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4 and evaporated in vacuo. The crude alkylated-phenol was then purified by flash column chromatography over silica gel (EtOAc/hexanes ˜1:3).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]([F:30])[C:15]3[N:16]([CH:27]=[N:28][CH:29]=3)[C:17]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([F:30])[C:15]2[N:16]([CH:27]=[N:28][CH:29]=2)[C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc(F)c3cncn3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a solution of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (298 mg, 0.55 mmol) in methanol (5 mL) was added hydrochloric acid in dioxane (2 mL, 4N, 8.0 mmol). The reaction mixture was stirred at room temperature for 1 hour then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (5 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×5 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preperative HPLC (10-90% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organics washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (83 mg, 30%). LCMS (Method A): RT=7.11 min, [M+H]+=505.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1>>[O:37]1[C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=[C:36]1[N:24]1[CH2:25][CH2:26][N:21]([C@H:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)=[O:14])[CH2:16][C@H:17]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23]1
Reactant: Clc1nc2ccccc2o1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(c3nc4ccccc4o3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=603.0 (M+H+), was prepared in accordance with the general method of example 59 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 2-chlorobenzoxazole.