Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(=O)(O)[O-].[Na+].[Cl:13][CH2:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])=[O:16]>O.CO>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([NH:17][C:15](=[O:16])[CH2:14][Cl:13])[CH:19]=1
Reactant: COC(=O)CN
Reactant: O=C(CCl)Nc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CNC(=O)c1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a mixture of glycine methyl ester hydrochloride (358 g., 2.85 mole) and 2.4 l. of water is added sodium bicarbonate (239.4 g., 2.85 mole). After stirring at room temperature for 0.5 hr., the mixture is diluted with 1 l. of methanol, cooled at 0° C. while sodium bicarbonate (239.4 g., 2.85 mole) is added followed by portionwise addition of 3-(chloroacetylamino)benzoylchloride (650 g., 2.8 mole) during a 0.75 hr. period. Considerable foaming takes place when approximately one-half of the acid chloride has been added and is controlled by periodic addition of small quantities of methanol. The reaction mixture is stirred for 16 hrs., diluted with 800 ml. of water and then stirred for an additional 0.5 hr. to provide a solid which is collected and sequentially washed with 500 ml. of 50% methanol, 2 l. of water, and 500 ml. of 50% methanol. The washed material is first air dried for 3 days and then for 12 hrs. under reduced pressure at 45° C. to afford 626.7 g. (77% yield) of N-[3-(chloroacetylamino)benzoyl]glycine methyl ester, m.p. 122.0°-124.0° C. Analytically pure N-[3-(chloroacetylamino)benzoyl]glycine methyl ester is obtained by crystallization from methanol, m.p. 122°-127° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([C@H:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]([O:29][CH3:30])=[O:28])=[C:21]([N:36]3[CH2:41][CH2:40][C:39]([CH3:46])([O:42][CH2:43][CH:44]=C)[CH2:38][CH2:37]3)[N:20]2[CH:47]=1)=[O:16])[CH2:2][CH:3]=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.[Pd]>[C:32]([O:31][C@@H:26]([C:22]1[C:23]([CH3:25])=[CH:24][C:19]2=[N:18][C:17]3=[CH:47][N:20]2[C:21]=1[N:36]1[CH2:37][CH2:38][C:39]([CH3:46])([O:42][CH2:43][CH2:44][CH2:3][CH2:2][CH2:1][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[CH2:13][NH:14][C:15]3=[O:16])[CH2:40][CH2:41]1)[C:27]([O:29][CH3:30])=[O:28])([CH3:35])([CH3:34])[CH3:33]
Reactant: C=CCCOc1ccc(F)cc1CNC(=O)c1cn2c(N3CCC(C)(OCC=C)CC3)c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc2n1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Pd]
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCCCOc1ccc(F)cc1CNC3=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A solution of methyl(2S)-2-[2-({[2-(but-3-en-1-yloxy)-5-fluorophenyl]methyl}carbamoyl)-7-methyl-5-[4-methyl-4-(prop-2-en-1-yloxy)piperidin-1-yl]imidazo[1,2-a]pyridin-6-yl]-2-(tert-butoxy)acetate (0.046 g, 0.071 mmol, 1 equiv) and TsOH monohydrate (15 mg, 0.077 mmol, 1.1 equiv) in DCE (24 mL) was heated to 75° C. The Hoveyda Grubbs 2nd generation catalyst (9 mg, 0.014 mmol, 0.2 equiv) was added. The pale green brown solution was stirred for 1 h. Upon cooling to ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in MeOH (5 mL) and 10% Pd/C (15 mg, 0.014 mmol, 0.2 equiv) was added. The reaction was then stirred under a balloon of H2 for 2 h. The reaction was then filtered through Celite eluting with MeOH. The filtrate was then concentrated in vacuo. The residue was taken up in DCM and washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (22 mg, 50%) as a brown film. LCMS (ESI, M+1): 625.35.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([CH3:19])=[CH:21][CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C)cc3)CC2)ccc1Cl
Yield: 56 %

Procedure:
The title compound (22 mg, 56%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-methylbenzoyl chloride. MS: 387.4 (MH+).
Reaction SMILES: [K].Br[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Br:9])[CH:8]=1.[CH3:10][CH:11]([OH:13])[CH3:12]>[Cu]>[Br:9][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([O:13][CH:11]([CH3:12])[CH3:10])[CH:8]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)O
Agent: [Cu]
Agent: [K]
Product: CC(C)Oc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
Under a nitrogen atmosphere, 2-propanol (30 mL) was added to potassium (2.4 g, 61.4 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. To the resulting solution was added 3,5-dibromopyridine (4.74 g, 20.0 mmol) and copper powder (250 mg, 3.9 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 70 h. Upon cooling to ambient temperature, the mixture was concentrated under high vacuum to a solid, which was diluted with water (200 mL) and extracted with diethyl ether (3×150 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a dark-brown oil (3.71 g). Purification by column chromatography on silica gel, eluting with 10→20% (v/v) diethyl ether in benzene afforded 1.38 g (31.9%) of 3-bromo-5-isopropoxypyridine as a volatile, colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][CH:5]2[CH:7]=[CH:8][C:9](=[O:10])[CH:4]2[O:3]1.N1C=CC=CC=1.[I:18]I.O>C(Cl)Cl.C1COCC1>[I:18][C:8]1[C:9](=[O:10])[C@@H:4]2[O:3][C:2]([CH3:11])([CH3:1])[O:6][C@@H:5]2[CH:7]=1
Reactant: CC1(C)OC2C=CC(=O)C2O1
Reactant: II
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2C=C(I)C(=O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3aR,6aR)-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (5-1) (1.2 g, 7.8 mmol, 1 equiv) was dissolved in DCM (50 mL) and pyridine (0.9 mL, 10.9 mmol, 1.4 equiv) was added followed by a solution of iodine (3.4 g, 13.2 mmol, 1.7 equiv) in THF (6 mL). The resulting mixture stirred overnight at ambient temperature. Upon disappearance of starting material, the reaction mixture was poured over water (30 mL), extracted with CHCl3 (3×50 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (80 g SiO2, 0-40% EtOAc in hexanes) to yield (3aR,6aR)-5-iodo-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (5-2) as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.97 (d, J=2.5 Hz, 1H); 5.22 (dd, J=5.5, 2.5 Hz, 1H); 4.53 (d, J=5.5 Hz, 1H); 1.42 (s, 3H); 1.39 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
A solution of 202 mg (0.994 mmol) 2-bromo-5-nitropyridine in 4 mL of toluene and 2 mL of EtOH was treated with 338 mg (1.09 mmol) 4-trifluoromethane-sulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Synthesis, 993, (1991)) and 1.49 mL (2.981 mmol) 2 M aqueous Na2CO3. The mixture was degassed via sonication, placed under argon, treated with 80.3 mg (0.00700 mmol) Pd(PPh3)4 and heated to 80° C. for 4 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting residue was chromatographed on a 50-g silica Varian MegaBond Elut column with 10-25% EtOAc-hexane to afford 226 mg (75%) of the title compound as a light yellow solid: Mass spectrum (ESI, m/z): Calcd. for C15H19N3O4, 306.1 (M+H), found 305.7.
Reaction SMILES: C(O[C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[CH:13]2)=[CH:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.CS([Cl:33])(=O)=O>C(O)C.ClCCl.O>[Cl:33][CH2:4][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[CH:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc2ccncc2c1
Reactant: CS(=O)(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: ClCc1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
196 mg (0.97 mmol) of 7-ethoxycarbonylisoquinoline obtained in step 1 was dissolved in 15 ml of ethanol. 110 mg (2.9 mmol) of lithium aluminum hydride was added to the solution under cooling with ice, and they were stirred at room temperature for 2 hours. Water was added to the reaction mixture and they were stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated. The obtained oily product was dissolved in 10 ml of dichloromethane. 0.26 ml (1.9 mmol) of triethylamine and 0.1 ml (1.3 mmol) of methanesulfonyl chloride were added to the obtained solution, and they were stirred overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9](N)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].OP=O.C(=O)([O-])[O-].[Na+].[Na+]>P(=O)(O)(O)O>[CH3:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(N)nc12
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Product: Cc1cccc2scnc12
Temperature: 25 °C

Procedure:
4-Methyl-2-amino-1,3-benzothiazole (4.93 g, 30 mmol) was dissolved in phosphoric acid (85%, 200 ml) with warming and vigerous stirring. The solution was cooled (-10°) and aqueous sodium nitrite (12.42 g in 35 ml water) added with stirring and cooling to maintain the temperature below -4°. The resulting solution was added dropwise, with vigerous stirring, to a cooled solution of hypophosphorus acid (50% by weight, 75 ml) at 0°. The reaction mixture was allowed to warm to ambient temperature and when evolution of gas was complete the mixture was diluted with ice-water, neutralised with sodium carbonate and extracted with dichloromethane (about 2.5 litres). Evaporation of the organic extracts, after drying over magnesium sulphate, gave an orange oil that was purified by chromatography on silica (dichloromethane as eluant). The product with adequate purity for further reaction was obtained as a dark orange oil.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][CH2:22]3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)CO>C(Cl)Cl>[CH:8]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23][CH2:22]3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C(O)CO)nc23)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=O)nc23)CC1
Reaction time: 0.17 h

Procedure:
Sodium periodate (0.34 mL, 0.22 mmol was added drop-wise to a slurry of silica gel (0.4 g) in DCM (3 mL)). The reaction was stirred for 10 minutes. tert-Butyl (1-(2-(1,2-dihydroxyethyl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (74 mg, 0.18 mmol) in DCM (2 mL) was then added to the slurry and the reaction was stirred for 30 minutes. The reaction was filtered and the collected solids were washed with DCM (20 mL). The filtrate was concentrated to give the crude product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[O:24]([CH:31]([CH3:35])[C:32](O)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:32](=[O:33])[CH:31]([O:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH3:35])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(Oc1ccccc1)C(=O)O
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C(C)Oc4ccccc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-phenoxy-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-phenoxypropionic acid (147 mg, 0.89 mmol). The title compound was obtained as white powder (15 mg, 4%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:20]2[C:28]3[CH:27]=[N:26][CH:25]=[N:24][C:23]=3[NH:22][CH:21]=2)=[O:19])[C:12]=1[F:29])C1C=CC=CC=1.COC(=O)NC1C=CC(F)=C(C(C2C3C=NC=NC=3NC=2)=O)C=1F.[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH2:10][C:11]1[C:12]([F:29])=[C:13]([C:18]([C:20]2[C:28]3[CH:27]=[N:26][CH:25]=[N:24][C:23]=3[NH:22][CH:21]=2)=[O:19])[C:14]([F:17])=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(F)c(C(=O)c2c[nH]c3ncncc23)c1F)OCc1ccccc1
Agent: COC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncncc23)c1F
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncncc23)c1F

Procedure:
The mixture of [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-carbamic acid benzyl ester (25) and [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-carbamic acid methyl ester (26) from the last step was dissolved in 30 mL of 1,4-dioxane and 25 mL of 10 N aqueous sodium hydroxide was added. The mixture was heated to reflux for 2 hours, then acidified with 6 N hydrochloric acid and adjusted to pH˜8 with addition of some sodium bicarbonate. This was extracted with ethyl acetate and the organic layer was washed with water and brine, then dried with magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the resulting residue was suspended in acetonitrile and sonicated for 30 minutes. The precipitated material was collected by filtration to provide the desired compound as a yellow solid (27, 263 mg). 1H-NMR(dmso-d6) was consistent with the desired compound. MS(ESI) [M+H+]=274.8.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([C:15]1[C:20]([O:21][CH2:22][CH3:23])=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:18]=[C:17]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[N:16]=1)=[O:14])[CH3:11]>C(Cl)(Cl)Cl>[CH2:10]([O:12][C:13]([C:15]1[C:20]([O:21][CH2:22][CH3:23])=[C:19]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:18]=[C:17]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:9])=[CH:34][CH:35]=2)[N:16]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Reactant: S=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(NC(=S)Nc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 60 %

Procedure:
Phenyl isothiocyanate (0.02 ml, 1.5 eq.) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (40 mg, 1 eq.) in CHCl3 (3 ml) and the mixture was reacted overnight at r.t. The reaction mixture was extracted with EA and washed with brine. The crude was purified by chromatography to give a product (32.6 mg, 60%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:19])[C@H:5]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH2:6].C(N(CC)CC)C.[NH:27]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[C@H:28]([C:41](ON1C(=O)CCC1=O)=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C)C=O>[NH:27]([C:51]([O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:52])[C@H:28]([C:41]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cold solution of Nε -t-butyloxycarbonyl-L-lysine methyl ester hydrochloride (H-Lys(Boc)-OMe.HCl) (0.89 g, 3 mmoles) and triethylamine (0.46 ml, 3.3 mmoles) in dimethyl-formamide (8 ml) is added Nα -benzyloxycarbonyl-Nε -t-butyloxy-carbonyl-L-lysine N-hydroxysuccinimide ester (Z-Lys(Boc)-OSu) (1.43 g, 3 mmoles) (Bull. Chem. Soc. Japan 39, 882 (1966)) and the mixture is allowed to stand at 4° C overnight followed by evaporation in vacuo at a bath temperature of 40° C. The residue is dissolved in ethyl acetate and the solution is washed successively with ice-cold M hydrochloric acid, water, and M sodium bicarbonate, dried over magensium sulfate and evaporated in vacuo to give a residue, which is precipitated from ethyl acetate-petroleum ether. Reprecipitation from the same solvent yields the desired product in pure form; yield 1.80 g (96.5%), [α]D22.5 -11.7°±0.5° (c 1.0, methanol). Thin-layer chromatography (silica gel): homogeneous (to ninhydrin after pretreatment with hydrobromic acid) in chloroform-methanol-acetic acid (90:10:3, v/v).
Reaction SMILES: [CH:1]1([C:4]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.O1CCOCC1.[ClH:28]>>[ClH:28].[CH:1]1([C:4]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(C2CC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(C2CC2)CCNCC1

Procedure:
1-tert-Butyl 4-ethyl 4-cyclopropylpiperidine-1,4-dicarboxylate (164 mg, 0.55 mmol) was stirred at rt in 4M Hydrogen chloride in dioxane (2 mL, 8 mmol) for 35 minutes. The volatiles were removed and the residue dried under high vacuum to afford the desired product as a crystalline solid (129 mg). 1H NMR (MeOD) δ 4.22 (q, J=7.1 Hz, 2H), 3.38 (dd, J=10.5, 2.7 Hz, 2H), 2.99-2.82 (m, 2H), 2.23 (dd, J=14.6, 2.2 Hz, 2H), 1.74 (td, J=14.3, 4.2 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.11-0.96 (m, 1H), 0.50-0.43 (m, 2H), 0.43-0.36 (m, 2H).
Reaction SMILES: C[Si](C)(C)[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[Cl:10][Si:11]([Cl:14])(Cl)Cl.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:10][Si:11]([Cl:14])([O:3][Si:4]([CH3:5])([CH3:6])[CH3:7])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: C[Si](C)(C)O[Si](C)(C)C
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: C[Si](C)(C)O[Si](Cl)(Cl)O[Si](C)(C)C
Yield: 19.8 %

Procedure:
About 1.9 ml of a 25% solution of phosphonitrile chloride in methylene chloride are added at room temperature with stirring to a mixture containing 486 g (3.0 mol) of hexamethyldisiloxane and 170 g (1.0 mol) of tetrachlorosilane. After the mixture has been stirred at room temperature for 8 hours, the catalyst is deactivated by adding 2.2 ml of tri-n-butylamine. Distillation of the reaction mixture at 18° to 34° C. and at 2 mbar gives 55 g of 3,3-dichlorohexamethyltrisiloxane, but no 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane. Likewise the desired 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane is neither found in the distillation residue (12 g) nor in the cold trap (583 g of a mixture of trimethylchlorosilane and 1,1,1-trichloro-3,3,3-trimethyldisiloxane).
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[F:17][C:18]([S:21]([O-:23])=[O:22])([F:20])[F:19].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:4]/[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2]\[CH2:1][S:21]([C:18]([F:20])([F:19])[F:17])(=[O:23])=[O:22]
Reactant: O=S([O-])C(F)(F)F
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CS(=O)(=O)C(F)(F)F
Reaction time: 66 h
Yield: 63 %

Procedure:
A mixture of 12.20 g (42.8 mmol) of Part B farnesyl bromide, 8.0 g (52 mmol, 1.2 equiv) of potassium trifluoromethylsulfinate (Parrish Chemical) and 1.00 g (4.3 mmol, 0.1 equiv) of 18-crown-6 in 200 mL of dry dimethylformamide was stirred for 66 hours. The dimethylformamide was evaporated at reduced pressure with minimal warming. The residue was dissolved in 600 mL of diethyl ether and washed with three 70 mL portions of H2O and 70 mL of brine, dried over MgSO4 and evaporated. Purification by flash chromatography on 200 g of Merck 9385 silica eluted with 15:85 CH2Cl2 : hexane provided 1.35 g of mixed fractions and 9.02 g (63%) of pure product. The mixed fractions were rechromatographed on 60 g of silica gel, eluting with 15:85 CH2Cl2 : hexane to provide 0.95 g (7%) of pure title product. The two portions of pure title triflone product were combined: 9.97 g (70%) of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:26]4([CH3:25])[CH2:29][O:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC1(N)COC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 91 %

Procedure:
As described for example 61b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (91 mg, 91%) which was obtained as a white solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[C:23]2[CH2:22][CH2:21][NH:20][CH:19]([CH3:24])[C:18]=2[O:17][CH:16]=1>>[Br:14][C:15]1[C:23]2[CH2:22][CH2:21][N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:19]([CH3:24])[C:18]=2[O:17][CH:16]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(Br)coc21
Product: CC1c2occ(Br)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-bromo-7-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine to provide the title compound.