Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC(C)([O-])C.[Na+].[Na+].[Cl-]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:12]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:8]1[C:6]2=[N:7][C:2]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:3][CH:4]=[C:5]2[CH:10]=[CH:9]1)([CH3:14])[CH3:13]
Reactant: C1COCCN1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(N3CCOCC3)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
In a 25 mL round-bottomed flask, 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (800 mg, 2.26 mmol, Eq: 1.00), palladium (II) acetate (254 mg, 1.13 mmol, Eq: 0.5) and tri-tert-butylphosphine (229 mg, 279 μl, 1.13 mmol, Eq: 0.5) were combined with toluene to give a yellow solution. Morpholine (789 mg, 789 μl, 9.06 mmol, Eq: 4) and sodium tert-butoxide (653 mg, 6.79 mmol, Eq: 3) were added. The reaction mixture was heated to 80° C. and stirred for 1 h. The reaction mixture was poured into 20 mL sat NaCl and extracted with EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 10% to 15% EtOAc in hexanes) to give 4-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (703 mg, 86%) as a light brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 0.24 ml of triethylamine and 0.12 ml of methanesulfonyl chloride were added and the mixture was stirred overnight at room temperature. Next, 0.24 ml of triethylamine and 0.12 ml of methanesulfonyl chloride were added to the reaction solution and stirring was continued at room temperature for 2 hours. The reaction solution was filtered with silica gel and NH silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (447 mg, 90% yield).
Reaction SMILES: [N:1]1O[C:3]([O-])=[C:4]2[N+:9]=1[CH2:8][CH2:7][O:6][CH2:5]2.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#C>CC1C=CC=CC=1C>[N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:12]=1[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C#CC(=O)OCC
Reactant: [O-]c1on[n+]2c1COCC2
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCOC2
Temperature: 140 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a partial solution of 6,7-dihydro-4H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazin-8-ium-3-olate (3.41 g, 24 mmol) in o-xylene (80 ml), was added ethyl propiolate (2.7 ml, 26 mmol). The mixture was stirred at 140° C. for 3 hr. An additional 2.0 ml (19 mmol) of ethyl propiolate was then added and the mixture was stirred at reflux for 18 hr. The final solution was evaporated under vacuum, and the residue was dissolved in a mixture of methylene chloride and hexanes (1:5). The solution was passed through a pad of silica gel and the filter pad was eluted with methylene chloride-hexanes, followed by ethyl acetate. The ethyl acetate eluent was evaporated and the residue washed with hexanes to give 4.10 g of a white solid; mp 63° C.; MS (ESI) m/z 197.1 (M+H).
Reaction SMILES: Cl.[C:2](=[NH:7])([O:4][CH2:5][CH3:6])[CH3:3].Cl.[F:9][C:10]([F:14])([F:13])[CH2:11]N.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:5]([O:4][C:2](=[N:7][CH2:11][C:10]([F:14])([F:13])[F:9])[CH3:3])[CH3:6]
Reactant: NCC(F)(F)F
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(C)=NCC(F)(F)F
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Ethyl acetimidate hydrochloride (1.23 g, 9.95 mmol) and 2,2,2-trifluoroethylamine hydrochloride (1.35 g, 9.95 mmol) were dissolved in CH2Cl2 (32 mL)/H2O (3.2 mL). K2CO3 (0.69 g, 4.98 mmol) was added and stirred for 30 minutes. The two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layer was dried with Na2SO4 and concentrated to give 1.48 g of N-(2,2,2-Trifluoro-ethyl)-acetimidic acid ethyl ester as a light yellow liquid in 87% yield.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>O1CCCC1.C(O)(C)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(C)s2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with a stream of nitrogen bubbling through it. A solution of dipropylamine (5.56 g, 0.055 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was stirred overnight at room temperature. The solvents were evaporated and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered, and evaporated to give a solid which was dissolved in hot isopropyl alcohol and filtered while hot. Addition of water and cooling caused a solid to precipitate. The solid was dissolved again in hot isopropyl alcohol with charcoal, filtered while hot and brought to the cloud point by addition of water. Upon cooling, solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 2.28 g (35%) of title compound, mp 125°-127° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])[CH3:2].[CH:9](OCC)=[O:10]>>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH:9]=[O:10])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC=O
Reactant: CCCC(=O)OCC
Product: CCOC(=O)C(C=O)CC

Procedure:
The title compound was prepared from butyric acid ethyl ester and ethyl formate employing the procedure set forth in Step 1 of Example 87.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19]([OH:21])=O)[CH:15]=1.Cl.[CH2:23]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH2:28])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH:28][C:19]([C:16]1[CH:15]=[C:14]([CH3:13])[O:18][N:17]=1)=[O:21])[CH3:24]
Reactant: Cc1cc(C(=O)O)no1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NC(=O)c1cc(C)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.2 g of 1,1'-carbonyldiimidazole (CDI) was added to a mixture of 6.35 g of 1B and 75 ml of dry tetrahydrofuran (THF) and the mixture was stirred for 2 hours at room temperature. Then 7.5 g of alanine ethyl ester hydrochloride was added, the mixture was stirred overnight, filtered, and the filtrate was stripped of solvent. The residue was dissolved in 100 ml of a 9:1 v:v mixture of methylene chloride and ethyl acetate, the solution was filtered through silica gel, the gel was washed with 900 ml of the same solvent, then the combined filtrate and washings was stripped of solvent. The residue was a yellow oil that crystallized on standing. The crystals were washed with pentane and dried, to give N-(5-methyl-3-isoxazolylcarbonyl)alanine ethyl ester (1C), as a solid, m.p.: 65°-66° C. 1C was converted to the corresponding acid (1D, a solid, m.p.: 148°-150° C.) in the manner that 1A was converted to 1B.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]1[C:38]([OH:40])=[O:39]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]5[C:38]([OH:40])=[O:39])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@H]1COCCN1
Product: O=C1N=C(N2CCOC[C@@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-3-(R)-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Morpholine-3-(R)-carboxylic acid following general procedure C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:12]1[N:13]=[C:14]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:15]2[NH:20][N:19]=[C:18](I)[C:16]=2[N:17]=1)[CH2:9][CH2:10][CH3:11].[Cl:34][CH2:35][CH2:36][CH2:37][C:38]#[CH:39]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:8]([C:12]1[N:13]=[C:14]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:15]2[NH:20][N:19]=[C:18]([C:39]#[C:38][CH2:37][CH2:36][CH2:35][Cl:34])[C:16]=2[N:17]=1)[CH2:9][CH2:10][CH3:11]
Reactant: C#CCCCCl
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(I)c2n1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCl)c2n1
Temperature: 25 °C
Yield: 155.1 %

Procedure:
Bis(triphenylphosphine)palladium(II)dichloride (101 mg, 0.144 mmol), triethylamine (0.403 mL, 2.89 mmol) and copper iodide (55.0 mg, 0.289 mmol) were added to a nitogen degassed solution of 5-butyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (900 mg, 1.926 mmol) in anhydrous N,N-dimethylformamide (23 mL). The mixture was stirred under a nitrogen atmosphere and heated to 60° C. before the addition of 5-chloropent-1-yne (296 mg, 2.89 mmol) in anhydrous N,N-dimethylformamide (2 mL). The reaction was stirred at 60° C. for 3 hours. A further 0.30 equivalents of 5-chloropent-1-yne (59 mg, 0.575 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added to the reaction. The mixture was stirred at 60° C. for a further 2.5 hours and then allowed to cool to room temperature overnight. The reaction mixture was evaporated in-vacuo to yield a brown oil. The resulting oil was partitioned between ethyl acetate (25 mL) and water/brine (1:1, 10 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a brown oil (1.32 g). The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 100 g silica cartridge and purified by chromatography using a 0-100% ethyl acetate in cyclohexane gradient over 60 minutes. Appropriate fractions were combined and evaporated in-vacuo to yield an orange oil. The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 100 g silica cartridge and re-purified by chromatography using a 0-100% ethyl acetate in cyclohexane gradient over 60 minutes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as an orange oil (720 mg).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:43]([NH:45][C@H:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH3:47])=[O:44])[CH2:41][OH:42])=[O:38])[CH2:28][CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:25])[CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>[Pd].CO>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:43]([NH:45][C@H:46]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH3:47])=[O:44])[CH2:41][OH:42])=[O:38])[CH2:28][CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:25])[CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 94 %

Procedure:
A solution of 8.0 g. (8.8 mmoles) of Z-28-32-OtBu in 160 ml. of methanol is hydrogenated in the presence of 1 g. of palladium-on-carbon. When the reaction terminates, the catalyst is filtered off, the filtrate is evaporated to dryness, and the residue is triturated with ether and petroleum ether. 6.4 g. (94 %) of H-28-32-OtBu are obtained. M.p.: 138-139°C; Rf12 = 0.1; [α]D = -9.7° (c = 1, in ethanol).
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[Cl-].C([N+](C(=O)CCCCCCC)(C(=O)CCCCCCC)C)(=O)CCCCCCC.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:11]([CH:10]([CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:9]([O:15][CH2:16][CH3:17])=[O:14])(=[O:12])[CH3:13]
Reactant: CCOC(=O)C(C)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: CCCCCCCC(=O)[N+](C)(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)C(C(C)=O)C(=O)OCC

Procedure:
Process according to claim 4 wherein ethyl chloropropionate is reacted with ethyl acetoacetate in a toluene mixture containing tricaprylyl methylammonium chloride as phase transfer agent, potassium iodide as iodide ion source, potassium carbonate, milled to below about 80 mesh as deprotonating base at 75° to 80° C. for a time sufficient to form diethyl α-acetyl-α'-methylsuccinate.
Reaction SMILES: [NH2:1]CC(O)=O.[CH3:6][O:7][C:8](=[O:19])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][F:18])[CH:12]=1.N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[F:18][CH2:17][C:13]1[CH:12]=[C:11]([N:10]([CH2:9][C:8]([O:7][CH3:6])=[O:19])[NH2:1])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CNc1cccc(CF)c1
Reactant: NCC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(N)c1cccc(CF)c1
Reaction time: 1 h

Procedure:
The glycine (Intermediate 54, 1 g, 5.1 mmol) was dissolved in acetic acid (10 ml) and water (1 ml) and cooled to ~5° C. Sodium nitrite (0.37 g, 5.4 mmol) in water (1.3 ml) was added to the glycine solution dropwise, maintaining the temperature at or below 5° C. The reaction was stirred at this temperature for 1 h. Zinc (1.33 g, 20.3 mmol) was then added slowly to the reaction keeping the temperature below 4° C., and the reaction was stirred for 1 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×100 ml) followed by saturated aqueous sodium bicarbonate (1×100 ml) then water (100 ml), dried (Na2SO4) and concentrated in vacuo to give an orange oil (1.06 g). The crude material was purified by chromatography on silica (Merck 9385, 28 g) eluted with ether-hexane 1:4 to give the title compound (Intermediate 55, 453 mg, 40%).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)(=O)C.I(C1C=CC=CC=1)=O.B(F)(F)F.[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])C>CO>[CH3:21][O:23][C:24](=[O:33])[CH:25]([O:3][CH3:1])[C:26]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)C1CCCC1
Agent: FB(F)F
Agent: O=Ic1ccccc1
Solvent: CO
Product: COC(=O)C(OC)C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared using a method analogous to that described in Tetrahedron 1998, 44, 1603-1607: To a suspension of iodosobenzene diacetate (5.2 g, 16.3 mmol) in MeOH (40 mL) was added BF3.0Et2 (2.1 mL, 16.3 mmol). The resulting mixture was added to 3-cyclopentyl-3-oxo-propionic acid ethyl ester (3.0 g, 16.3 mmol) and stirred at rt overnight. The mixture was concentrated to half the total volume, quenched with satd. aq. NaHCO3, and extracted with CHCl3 (2×). The combined organic layers were dried and concentrated and the crude residue purified (EtOAc/hexanes) to yield a colorless oil (1.5 g, 43%). 1H NMR (MeOD): 4.4 (s, 1H), 3.8 (s, 3H), 3.5 (s, 3H), 3.3-3.2 (m, 1H), 1.9-1.5 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]1([NH2:19])[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:19][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
5-Bromo-2-fluoro-benzoic acid (4.96 g, 22.6 mmol), benzene-1,2-diamine (4.90 g, 45.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (5.21 g, 27.2 mmol), 1-hydroxybenzotriazole hydrate (1-HOBt) (3.67 g, 27.2 mmol) and dimethyl-pyridin-4-yl-amine (DMAP) (0.03 g, 0.2 mmol) were placed into a 100 mL round bottom flask. Dry DMF (60 mL) was added and the reaction was stirred at room temperature overnight. Solvent was removed under reduced pressure, then the crude diluted with DCM (15 mL) and 0.4 M Na2CO3 solution (15 mL) A white precipitate formed and it was filtered off and washed again with DCM (10 mL) and dried to afford 4.96 g of the title compound. Solutions were collected, the organic phase was separated from the aqueous one and concentrated under reduced pressure: other precipitate formed and it was filtered off, washed with DCM (3 mL) to afford other 0.68 g of desired compound. Total yield 81%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][C:27]([F:30])([F:29])[F:28])[N:19]=1>C(#N)C>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([O:26][C:27]([F:29])([F:28])[F:30])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: COc1cc(OC(F)(F)F)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC(F)(F)F)n1
Reaction time: 12 h
Yield: 47.7 %

Procedure:
4.8 g (0.02 mol) of 2-methoxycarbonylbenzenesulfonyl isocyanate in 10 ml of acetonitrile were added over the course of 15 minutes to a stirred mixture of 4.1 g (0.02 mol) of 2-amino-4-methoxy-6-trifluoromethoxypyrimidine and 100 ml of acetonitrile at 25° C., and the mixture was then stirred for 12 hours. The precipitate was removed (2.4 g of melting point 141-143° C.) and then the filtrate was concentrated under reduced pressure and stirred with ether/petroleum ether, and the solid was filtered off with suction and dried. A further 4.3 g of the title compound of melting point 141-143° C. were obtained. The total yield was 6.7 g (74.4% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([SH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][S:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](COS(C)(=O)=O)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](CSCc2ccccc2)[C@@H](O)C1
Reaction time: 1 h

Procedure:
(3R,4R)-1-tert-Butoxycarbonyl-3-hydroxy-4-(mesyloxymethyl)pyrrolidine (see Example 34, 1.10 g, 3.7 mmol) was dissolved in DMF (2 mL) and added dropwise to a solution of benzyl mercaptan (870 μL, 7.4 mmol) and NaH (270 mg, 60% oil dispersion, 6.8 mmol) in DMF (10 mL) and stirred at room temp. for 1 h. The reaction was diluted with toluene, washed with water then brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4S)-1-tert-butoxycarbonyl-3-hydroxy-4-(benzylthiomethyl)pyrrolidine as a syrup. Without further characterisation, the product was dissolved in MeOH (5.0 mL) and cHCl (1.0 mL) and concentrated in vacuo to afford (3R,4S)-3-hydroxy-4-(benzylthiomethyl)pyrrolidine hydrochloride (53) as a syrup (730 mg, 76% overall yield for two steps). 1H NMR (D2O) δ 7.40-7.27 (m, 5H), 4.26-4.22 (m, 1H), 3.74 (s, 2H), 3.56 (dd, J=12.4, 7.2 Hz, 1H), 3.37 (dd, J=12.8, 5.2 Hz, 1H), 3.21 (dd, J=12.8, 3.0 Hz, 1H), 3.07 (dd, J=12.4, 5.5 Hz, 1H), 2.61-2.52 (m, 1H), 2.47-2.34 (m, 2H). 13C NMR (D2O). δ 138.7, 129.5, 129.3, 127.9, 73.5, 51.5, 48.5, 45.4, 35.9, 31.8. (MH+) calc for C12H18NOS: 224.1109. Found 224.1102.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH:6]=1.C([O:9][CH:10]=[C:11]([C:17]#[N:18])[C:12](OCC)=O)C>C(O)C>[C:17]([C:11]1[C:10](=[O:9])[N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[N:1][CH:12]=1)#[N:18]
Reactant: NC1=CCCN1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: N#Cc1cnc2n(c1=O)CCC2
Temperature: -5 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
16.8 g of 2-amino-pyrroline are dissolved in 140 ml of ethanol and the solution is cooled to -5° C. and under stirring added dropwise to a solution of 33.8 g of ethyl ethoxy-methylene-cyanoacetate in 250 ml of ethanol. The reaction mixture is allowed to warm up to room temperature, and boiled for one hour. The reaction is then allowed to crystallize under cooling below 0° C. The precipitated crystals are filtered and thus 13.7 g (42.5%) of 3-cyano-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine are obtained, melting at 119°-121° C. after recrystallization from ethanol.