Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([C:20]23[CH2:27][CH2:26][C:23]([CH2:28][CH2:29][OH:30])([CH2:24][CH2:25]2)[CH2:22][O:21]3)[CH:10]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:12]=1>C(Cl)Cl>[CH3:1][S:2]([O:30][CH2:29][CH2:28][C:23]12[CH2:24][CH2:25][C:20]([C:9]3[CH:10]=[C:11]([O:13][CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][O:15]4)[CH:12]=[C:7]([F:6])[CH:8]=3)([CH2:27][CH2:26]1)[O:21][CH2:22]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Solvent: ClCCl
Product: CS(=O)(=O)OCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methanesulfonyl chloride (0.100 mL, 1.28 mmol) was added to a solution of 2-(1-(3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethanol (36G; 0.373 g, 1.06 mmol) and TEA (0.46 mL. 3.19 mmol) in DCM (5 mL) at 0° C. and the reaction was stirred at 0° C. for 2 h and then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with 1 N aq. HCl and water, sat. aq. NaHCO3, and water again. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give the crude title compound (0.456 g, 1.06 mmol, 100% yield) as a clear oil.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH:29]=3)=[N:27][N:26]([CH3:30])[C:25]=4[CH3:31])[N:14]=2)[CH2:2]1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:19][C:18]1[C:13]([NH:12][CH:3]2[CH2:4][CH2:5][C:6]3([CH2:7][CH2:8][N:9]([C:39](=[O:41])[CH3:40])[CH2:10][CH2:11]3)[CH2:1][CH2:2]2)=[N:14][C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[C:28]([CH:29]=2)=[N:27][N:26]([CH3:30])[C:25]=3[CH3:31])=[N:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CCNCC5)CC4)n3)cc2nn1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CCC(Nc3nc(Nc4ccc5c(C)n(C)nc5c4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a suspension of N4-(9-azaspiro[5.5]undecan-3-yl)-5-chloro-N2-(2,3-dimethylindazol-6-yl)pyrimidine-2,4-diamine (0.10 g, 0.23 mmol) in anhydrous DCM (10.0 mL) were added N,N-diethylethanamine (0.036 g, 0.35 mmol) and acetyl acetate (0.029 g, 0.29 mmol). The mixture was stirred at room temperature for 30 min then diluted with DCM (40 mL), washed with water (20 mL×2), followed by saturated NaHCO3 (20 mL) and brine (20 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1 to 15/1) to give the title compound as a light green solid (75 mg, 68%).
Reaction SMILES: C[S-:2].[Na+].Br[C:5]1[CH:6]=[C:7]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:8]=[N:9][CH:10]=1>CN(C)C=O>[SH:2][C:5]1[CH:6]=[C:7]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:8]=[N:9][CH:10]=1
Reactant: C[S-]
Reactant: CN(C)C(=O)c1cncc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cncc(S)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Sodium thiomethoxide (3 g) was added to a stirred solution of 5-bromo-N,N-dimethyl-3-pyridinecarboxamide (2.5g, WO2000055168) in N,N-dimethylformamide (40 ml) and the suspension stirred at 100° C. for 4 h. The solvent was concentrated in vacuo, the residue dissolved in 2M sodium hydroxide (35 ml) and water (50 ml), and the solution washed with chloroform (4×75 ml). The aqueous layer was acidified with 2M hydrochloric acid to pH 4 and extracted with chloroform (5×80 ml), and the combined organic layers were washed with brine (20 ml), dried over magnesium sulphate and concentrated in vacuo to give the title compound as an orange oil (1.8 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[C:66]([CH3:68])[CH:65]=[CH:64][C:63]=3[CH3:69])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])[C@@H:41]([O:52][C:53]2[N:58]=[CH:57][N:56]=[C:55]3[N:59]([C:62]4[CH:67]=[C:66]([CH3:68])[CH:65]=[CH:64][C:63]=4[CH3:69])[N:60]=[CH:61][C:54]=23)[CH2:40][O:39][CH2:38][CH2:37][OH:36])=[N:46][CH:47]=1
Reactant: Cc1ccc(C)c(-n2ncc3c(O[C@@H](COCCO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(=O)Nc4ccc(Cl)cn4)ncnc32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(-n2ncc3c(O[C@@H](COCCO)C(=O)Nc4ccc(Cl)cn4)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.455 mL, 0.45 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(2,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AJ1) (328 mg, 0.45 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (2 mL), diluted with DCM (25 mL) and poured onto a phase separator. The organic layer was loaded onto a silica column and purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane. This was further purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (93 mg, 42.4%). 1H NMR (400 MHz, DMSO) δ 2.00 (3H, s), 2.33 (3H, s), 3.53 (2H, m), 3.57-3.68 (2H, m), 4.03 (1H, m), 4.11 (1H, m), 4.66 (1H, t), 5.92 (1H, m), 7.23 (1H, s), 7.28 (1H, d), 7.34 (1H, d), 7.90 (1H, dd), 8.02 (1H, d), 8.41 (1H, d), 8.52 (1H, s), 8.57 (1H, s), 11.23 (1H, s). m/z (ES+) (M+H)+=481; HPLC tR=2.35 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1>>[C:4]1([C:1](=[N:11][O:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccc1

Procedure:
Following a procedure similar to that described in Example 40(f), 0.16 ml of acetophenone was reacted with 400 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was mixed with diisopropyl ether and the mixture was stirred. The precipitated powder was collected by filtration, to give 370 mg of the title compound.
Reaction SMILES: C(C1C=CC=C(C(C)C)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+].[CH:31]([C:34]1[C:42]2[O:41][CH:40]([CH2:43][OH:44])[CH2:39][C:38]=2[CH:37]=[CH:36][CH:35]=1)([CH3:33])[CH3:32].[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>>[CH3:55][C:45]1[CH:50]=[CH:49][C:48]([S:51]([O:44][CH2:43][CH:40]2[CH2:39][C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([CH:31]([CH3:33])[CH3:32])[C:42]=3[O:41]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1cccc2c1OC(CO)C2
Agent: C=CCc1cccc(C(C)C)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(C(C)C)c3O2)cc1
Yield: 79 %

Procedure:
Treatment of 2-allyl-6-isopropylphenol (8.81 g, 0.05 mmol) with 3-chloroperoxybenzoic acid (22.43 g, 0.13 mol, 77%)) followed by potassium carbonate (13.82 g, 0.1 mol) generally according to the procedure described for Intermediate 9 provided (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (3.45 g, 0.018 mol) with p-toluenesulfonyl chloride (3.92 g, 0.021 mol) generally according to the procedure described for Intermediate 10 afforded 4.91 g (79%) (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C19H22O4S C, 65.87; H, 6.4. Found C, 65.63; H, 6.32.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[S:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]>C1COCC1.O=[Mn]=O>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[S:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CO)s4)cc23)CC1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)s4)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1H-indole-7-carboxamide (200 mg, 0.46 mmol) in THF (5.0 mL) was added MnO2 (1.21 g, 13.9 mmol). The mixture was stirred at room temperature for 3 h. Filtration of reaction mixture thru celite afforded 100 mg of the title compound (48.8%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[CH3:27][C:28]1[CH:29]=C[C:31](S(O)(=O)=O)=[CH:32][CH:33]=1.C(N(CC)CC)C.C=C1CC(C(Cl)=O)C1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(C)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:27]([CH:28]3[CH2:33][C:32](=[CH2:31])[CH2:29]3)[S:9][C:3]=2[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc(Br)cc1S
Agent: C=C1CC(C(=O)Cl)C1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: Cc1ccc(C)cc1
Product: C=C1CC(c2nc3ccc(Br)cc3s2)C1
Temperature: 50 °C
Yield: 250.1 %

Procedure:
The product of Example 1A (1.0 g, 4.90 mmole) was weighed into a 100 ml round bottom flask and pyridium p-toluenesulfonate (0.37 g, 1.47 mmole) was added. The flask was placed on high vacuum overnight. Para-xylene (50 ml) was added followed by triethylamine (0.68 ml, 4.9 mmole). The mixture was rapidly stirred at 50° C. to give an almost clear solution. A solution of 3-methylene-cyclobutanecarbonyl chloride (0.64 g, 4.9 mmole) (prepared according to literature procedure, JACS, 1959, 81, 2723-2728) in 10 ml xylene was then added dropwise over 15 minutes. The temperature was raised to 140° C. for 7 hours. The mixture was cooled to room temperature, followed by the addition of ethyl acetate (100 ml). The resulting solution was washed with saturated sodium bicarbonate, and the organic layer was dried (Na2SO4), and concentrated to give an oil. The crude product was purified by chromatography (20% hexane in dichloromethane) to give the title compound (1.03 g, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 7.98 (d, J=2.03 Hz, 1H), 7.83 (d, J=8.82 Hz, 1H), 7.55 (dd, J=8.82, 2.03 Hz, 1H), 4.83-4.98 (m, 2H), 3.83-4.04 (m, 1H), 3.10-3.35 (m, 4H). MS: (M+H)+=279/281.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[OH:11]O.C=O>C(O)(=O)C>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N+:2]=1[O-:11]
Reactant: c1cc2c(cn1)CCCC2
Reactant: OO
Agent: C=O
Solvent: CC(=O)O
Product: [O-][n+]1ccc2c(c1)CCCC2
Temperature: 97.5 °C
Yield: 86 %

Procedure:
5,6,7,8-Tetrahydroisoquinoline (13.3 g, 100 mmole) is dissolved in 35 ml glacial acetic acid in a 200 ml one neck round bottom flask. The solution is warmed to 95-100° C. and is treated dropwise with 30% hydrogen peroxide (28 ml). The reaction is stirred at 95-100° C. for 6h, is treated portionwise with paraformaldehyde until negative to starch iodide paper, and the volatiles are removed in vacuo. The residue is azeotroped with 2×100 ml toluene and the crude material is chromatographed over 500 g silica gel (230-400 mesh), eluting with 4 l 6% methanol/dichloromethane followed by 1 l 10% methanol/dichloromethane while collecting 50 ml fractions. Fractions 39-82 are combined and concentrated to afford 12.8 g (86%) of 5,6,7,8-tetrahydroisoquinoline-N-oxide.
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[CH:19][C:5]([O:6][CH2:7][CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][C:3]=1[CH3:22].FC(F)(F)C(O)=O>ClCCl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[C:20]([CH3:21])=[CH:19][C:5]([O:6][CH2:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(OCC2CN(C(=O)OC(C)(C)C)C2)cc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCC2CNC2)cc(C)c1Br
Temperature: 0 °C
Reaction time: 6 h

Procedure:
tert-Butyl 3-((4-bromo-3,5-dimethylphenoxy)methyl)azetidine-1-carboxylate (900 mg) and trifluoroacetic acid (0.3 mL) are dissolved in dichloromethane (40 mL). The reaction mixture is stirred at 0° C. for 6 hours, diluted with a saturated aqueous solution of NaHCO3, dried (MgSO4) and concentrated to give the title compound. Yield: 400 mg.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][S:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH3:19][S:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:23][CH:22]=1
Reactant: CSc1ccc(N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: CSc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-methylthioaniline as the starting materials.
Reaction SMILES: [C:1]([O-:4])([OH:3])=O.[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.O=[C:18]1[CH:25]2[CH2:26][C:21]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)C2.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:3]=[C:1]1[CH:25]2[CH2:26][C:21]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:20][CH:19]([CH2:27][CH:23]([CH2:22]3)[O:4]1)[CH2:18]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)OC(=O)C(C3)C2
Temperature: 25 °C
Yield: 85 %

Procedure:
Solid NaHCO3 (0.3 mol) and mCPBA (0.3 mmol, 77% purity) were added to a solution of ketone 1C (0.19 mmol) in DCM (5 mL) t 0° C. The reaction mixture was allowed to warm to rt and was maintained for 1 h. The reaction mixture was diluted with a saturated, aqueous solution of sodium bisulfate (10 mL) and was extracted with DCM (3×5 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (10/90 to 30/70 EtOAC/hexane) to provide lactone 13A in 85% yield. Data: LC/MS (ESR) m/z 282 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:26])=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.CO[CH:29]1[CH2:33][CH2:32][CH:31](OC)O1>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:26]2[CH:29]=[CH:33][CH:32]=[CH:31]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1-n1cccc1
Temperature: 110 °C
Yield: 88 %

Procedure:
6-Chloro-2-{4-[2-(4-morpholinyl)ethoxy]phenyl}-1H-imidazo[4,5-b]pyridin-7-amine (Example 212) (17 mg, 45 μmol) was dissolved in acetic acid (5 ml). 2,5-Dimethoxytetrahydrofuran (0.20 ml) was added and the mixture heated (110° C., 3 h) and then allowed to cool and the solvents and excess reagents were removed in vacuo. The residual brown oil was dissolved in acetonitrile (1 ml) and subjected to semi-preparative HPLC-C18. The appropriate fractions were pooled and evaporated in vacuo. The residue was dissolved in EtOAc (5 ml). This solution was washed with saturated aqueous NaHCO3 (5 ml) and brine (2 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to afford the pure product (17 mg, 88%) as a beige powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[N:15](CC3C=CC(C(F)(F)F)=CC=3)[N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O>>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)O
Yield: 94 %

Procedure:
Following the procedure as described in Example 20, making variation as required to replace ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 94% yield: MS (ES−) m/z: 225.0 (M−1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:26]([NH:28][C@H:29]([C:45]([O:47]CC1C=CC=CC=1)=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)=[O:27])[CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)=[O:17])[CH2:7][O:8]CC1C=CC=CC=1)=[O:4].CO.C(O)(=O)C.O>[H][H].[Pd]>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:26]([NH:28][C@H:29]([C:45]([OH:47])=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])=[O:27])[CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)=[O:17])[CH2:7][OH:8])=[O:4]
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: NCCCC[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)CN)C(=O)O
Yield: 70.7 %

Procedure:
10.5 g of palladium-on-charcoal was added to 23.2 g of Z-Gly-Ser(Bzl)-His-Lys(Z)-OBzl (Compound 11) suspended in a mixed solvent of 160 ml of methanol, 40 ml of acetic acid and 20 ml of water, and stirring was continued under atmospheric pressure in hydrogen atmosphere for 38 hours. After the catalyst was filtered off, the filtrate was washed with water and concentrated. The crude product was dissolved in water and eluted with 0.5N ammonia water using a strongly acidic ion exchange resin (NH4 +type). The eluate was concentrated and crystallized to obtain 8.0 g of Gly-Ser-His-Lys (Compound 20).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:43][O:42][C:40]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)=[O:41]
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)CC1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.07 g, 0.151 mmol) was suspended in DCM (1.5 mL) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) was added. Methyl chloroformate (0.018 mL, 0.227 mmol) was added and the resulting solution stirred at RT. After 4 hours the solvent was evaporated. The remaining oil was purified by SiO2 chromatography (11 g SiO2, DCM/MeOH 0-4% MeOH). Obtained 0.052 g of 4-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-ureido}-piperidine-1-carboxylic acid methyl ester as light brown foam (76% yield).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].[O:36]1[CH2:38][CH:37]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:38][CH:37]([OH:36])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: c1ccc(C2CO2)cc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(CC(O)c3ccccc3)CC2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
A mixture of compound 15 (0.005 mol) and 1,2-epoxyethylbenzene (0.006 mol) in methanol (50 ml) was stirred at RT for 1 hour. The mixture was stirred and refluxed for 3 hours. The solvent was evaporated and the residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 95/5). Two pure fractions were collected and their solvents were evaporated. Each residue was dried, yielding 0.7 g (23%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-2-phenylethyl)-1piperazinyl]-2-(phenylmethyl)piperidine (compound 60) and 0.23 g (7%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-2-phenylethyl)-1piperazinyl]-2-(phenylmethyl)piperidine (compound 61).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[K+].O>C(O)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCCCCCCC1=C(C)CCCC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=C(CCCCCCCCC(=O)O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To ethyl 9-(2,6,6-trimethylcyclohex-1-en-1-yl)nonanoate (13.2 g, 42.9 mmol) in ethanol (80 mL) was added 4 M KOH (43 mL). The mixture was stirred at room temperature for 1.5 h. Water (350 mL) was added and the solution was washed with tert-butyl methyl ether (2×100 mL). The SimVA, aqueous phase was cooled, acidified with 4 M HCl (˜45 mL) and extracted with pentane (3×100 mL). The combined pentane extracts were washed with water (200 mL), dried (MgSO4), filtered, concentrated and dried under high vacuum. The material was redissolved in pentane (100 mL), concentrated and dried under high vacuum one more time to give 9-(2,6,6-trimethylcyclohex-1-en-1-yl)nonanoic acid as a colorless oil (11.1 g, 92% yield). MS ESI− m/z 279 [M−H]−.