Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].C([NH:41][CH2:42][CH2:43]Br)(OC(C)(C)C)=O>C(#N)C>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:43][CH2:42][NH2:41])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OCCN
Temperature: 80 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
To a mixture of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (700 mg, 1.82 mmol) and K2CO3 (760 mg, 5.45 mmol) in acetonitrile (14 mL), 2-(Boc-amino)-ethylbromide (839 mg, 3.63 mmol) is added. The mixture is stirred at 80° C. for 12 h. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in DCM (10 mL) and treated with TFA (1.4 mL). The mixture is stirred at rt for 19 h before another portion of TFA (0.7 mL) is added. Stirring is continued at rt for another 21 h. The mixture is diluted with DCM and washed with 1 M aq. NaOH. The washing is extracted back with DCM. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC. The product containing fractions are combined, concentrated, dissolved in methanol:water 9:1 and filtered over Amberlyst A-21. The filtrate is evaporated and dried to give the title compound (513 mg) as a pale yellow resin; LC-MS: tR=0.44 min; [M+1]+=429.20; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 1.23 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.35 (s, 3H), 2.58 (q, J=7.3 Hz, 4H), 2.73 (q, J=7.5 Hz, 2H), 3.05 (t, J=5.5 Hz, 2H), 3.73 (s, 3H), 3.86 (t, J=5.5 Hz, 2H), 7.75 (s, 2H), 7.80 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[N:16]=[CH:15][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH:23]=O)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:21]=2)(=[O:19])=[O:18])=[CH:15][N:16]=1
Reactant: O=Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-({6-[(E)-2-(2,4-Difluorophenyl)vinyl]pyridin-3-yl}sulfonyl)benzaldehyde (Step 1, 95 mg, 0.25 mmol) was suspended in methanol (1 mL) and acetic acid (70 μL). Morpholine (28 μL, 0.34 mmol) was added and the reaction stirred at room temperature under nitrogen for 30 minutes. Sodium cyanoborohydride (15 mg, 0.25 mmol) was added and stirring continued for 2 days. 5N sodium hydroxide was added and the products extracted into dichloromethane, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography (90% ethyl acetate/isohexane) gave the title compound as a yellow foam which was treated with ethereal HCl to give the hydrochloride salt (8 mg, 7%). δH (500 MHz, d6 DMSO): 11.24 (1H, s), 9.11 (1H, d, J=2.1 Hz), 8.38 (1H, dd, J=2.1, 8.2 Hz), 8.33 (1H, s), 8.08 (1H, d, J=7.8 Hz), 7.93 (2H, q, J=8.0 Hz), 7.87 (1H, d, J=16.1 Hz), 7.76-7.70 (2H, m), 7.46 (1H, d, J=16.1 Hz), 7.37-7.31 (1H, m), 7.18 (1H, td, J=2.1, 8.4 Hz), 4.43 (2H, s), 3.91 (2H, d, J=11.8 Hz), 3.74 (2H, t, J=11.8 Hz), 3.20 (2H, d, J=11.6 Hz), 3.12-3.06 (2H, m); m/z (ES+) 457 [MH+].
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([O:10]C)=[O:9])[C:3]([O:5]C)=[O:4].[OH-].[Li+]>O1CCCC1.O>[CH3:1][CH:2]([CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(=O)O)C(=O)O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
Commercially available dimethyl methylsuccinate (1.57 g, 9.8 mmol) was dissolved in a 3:1 mixed solvent of tetrahydrofuran and water, and lithium hydroxide (4 g, 98 mmol) was added and stirred for 2 days at 40° C. under reflux. After completion of the reaction was confirmed by TLC, the residue was distilled under reduced pressure to afford the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(OCC)(=O)C.[ClH:28]>C(OCC)C>[ClH:28].[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1cc(CCN2CCNCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Alternatively, 1-Boc-4-[2-(4-pyridinyl)ethyl]piperazine (1.0 g, 3.43 mmol) was dissolved in ethyl ether. Ethyl acetate (15 mL) saturated with HCl was added, and the mixture stirred for 30 min at room temperature. The mixture was concentrated under vacuum and provided 1-[2-(4-pyridinyl)ethyl]piperazine hydrochloride (900 mg, 87%) as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:4]1[N:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCOC(=O)c1ncc(CC)[nH]1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1nc(Br)c(CC)[nH]1
Yield: 69 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-ethyl-1H-imidazole-2-carboxylate obtained by the method described in Example (1b) (0.29 g, 1.30 mmol) and NBS (0.28 g, 1.28 mmol), to obtain 0.22 g of the title compound as a white solid (69%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([N:18]1[CH2:22][CH2:21][O:20][C:19]1=[O:23])(=[O:17])[CH:13]=[CH:14][CH2:15][CH3:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:14]([CH2:15][CH3:16])[CH2:13][C:12]([N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])=[O:17])=[CH:5][CH:4]=1
Reactant: CCC=CC(=O)N1CCOC1=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCC(CC(=O)N1CCOC1=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 4-trifluoromethylaniline (193 mg, 1.2 mmol) and 3-(2-pentenoyl)-1,3-oxazolidin-2-one (189 mg, 1.0 mmol) in toluene (3 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (26.6 mg, 0.025 mmol), and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was then evaporated off and the crude product obtained was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective compound 3-[3-(4-trifluoromethylanilino)pentanoyl]-1,3-oxazolidin-2-one (165 mg, 50% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: OA-2000) to be 70% e.e.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)=O.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].O>OS(O)(=O)=O.C(O)(=O)C>[C:2]([CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)(=[O:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCCC(=O)[c-]1cccc1)c1ccccc1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccccc1)C1CCCC=C1[c-]1cccc1
Reaction time: 8 h
Yield: 36.2 %

Procedure:
7-Oxo-7-phenylheptanoylferrocene (1.94g; 5 mmole) was dissolved in 5% H2SO4 /acetic acid (40 ml; excess) at room temperature. The solution was stirred overnight and then poured into water (400 ml) and extracted with chloroform (3 × 200 ml). The organic layers were extracted with water, saturated aqueous sodium bicarbonate, and water, and dried (Na2SO4) to yield a brown oil. The crude occurrence product was suspended in hot petroleum ether (bp 40°-60° C.) and filtered. The filtrate was submitted to preparative thin layer chromatography on silica. The main yellow band was eluted with petroleum ether/ethyl acetate (10:1) and gave 670 mg (36.2%) of pure 3-benzoyl-2-ferrocenylcyclohexene mp 127°-129° C. EXAMPLE 8
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[OH:12][CH2:13][C:14]1[C:18]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]3=[O:35])[CH:21]=[CH:22][C:17]=2[S:16][N:15]=1.CN1C(C(F)(F)F)=CC(=[O:47])N(C2C=CC3SN=C(C=O)C=3C=2)C1=O>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH3:34][N:25]1[C:26]([C:30]([F:32])([F:31])[F:33])=[CH:27][C:28](=[O:29])[N:23]([C:20]2[CH:21]=[CH:22][C:17]3[S:16][N:15]=[C:14]([C:13]([OH:47])=[O:12])[C:18]=3[CH:19]=2)[C:24]1=[O:35]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CO)c3c2)c1=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of potassium dichromate (10.0 g) in 1.5 M sulfuric acid (200 mL) is cooled to 0° C., treated dropwise with a solution of a 2:3 mixture of 3-[3-(hydroxymethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (12.0 g) in acetic acid, stirred at room temperature for 2 hours, and diluted with water. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a white solid (8.50 g, mp 149-152° C.).
Reaction SMILES: ClC1C=C(CCC[N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:43](O)=O)=[CH:36][CH:35]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][N:11]([CH:25]2[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:38][CH:39]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-methoxy-phenyl)-butyric-acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4](I)[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([O:21][CH3:22])[CH:13]=1>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=2[O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CNc1cnc(Cl)cc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnc(Cl)cc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine (prepared according to WO2006013050) and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Off-white solid (81%). MS (ESI): m/z=267.07 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CC(C)=O>[Cl:15][CH2:16][CH2:17][C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][CH:14]=1)=[O:19]
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: O=C(Cl)CCCl
Solvent: CC(C)=O
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCCl)cc1
Yield: 74 %

Procedure:
19.2 g (100 millimoles) of 3-(p-aminobenzoyl)-propionic acid were stirred with 24.8 g (195 millimoles) of 3-chloropropionyl chloride in 200 ml of absolute acetone for 10 hours at room temperature. The mixture was then evaporated down, the residue was stirred with 200 ml of water, and the product was filtered off under suction at 10° C., washed with cold acetone and dried at 100° C. under reduced pressure. 21 g (75%) of 3-[p-(3-chloropropionylamino)-benzoyl]-propionic acid were obtained as yellowish crystals of melting point 181°-182° C. (acetonitrile).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F
Yield: 74.7 %

Procedure:
A mixture of 0.073 g (0.38 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 ml of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 112 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 75%).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1>[OH-].[Na+].CS(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[S:1][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Sc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccnc1Sc1ncccn1
Temperature: 82 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of 2.8 g of 2-mercaptopyrimidine in 35 ml 5.5% aqueous sodium hydroxide solution was added to 3.95 g 2-chloro-3-nitropyridine in 15 ml DMSO that was preheated to 92° C. The mixture, already containing precipitated product, cooled, and then was reheated to reflux at 82° C. After one hour, the reaction was allowed to cool and then poured into 150 ml ice-water. The precipitate was collected by filtration, washed with water and 95% ethanol, and then recrystallized from 95% ethanol to give 4.34 g (74% yield), mp 122.5°-124° C.
Reaction SMILES: CN(C)C=O.CC(C)([O-])C.[Na+].[CH3:12][CH2:13][O:14][C:15]([CH:17](P(OCC)(OCC)=O)[CH3:18])=[O:16].[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>O>[CH3:18][C:17](=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=1)[C:15]([O:14][CH2:13][CH3:12])=[O:16]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(C)cc1
Temperature: -2.5 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To dimethylformamide (1802 ml) that had been cooled to −10° C. was added sodium tert-butoxide (528.6 g) and the solution was stirred at −5 to 0° C. for 30 min. Triethyl 2-phosphonopropionate (1310 g) was added dropwise thereto at 10° C. or below. The solution was stirred at 2 to 5° C. for 1 hr, and 4-methylbenzaldehyde (600.8 g) was added dropwise thereto at 10° C. or below and the solution was stirred at room temperature for 1 hr. Water was added thereto and the solution was extracted with toluene. The extract was washed with water and the solvent was distilled off to give the title compound as an oil (1009 g, yield 98.8%).
Reaction SMILES: O[CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(Cl)Cl.C(N(S(F)(F)[F:30])CC)C>[Cl-].[Na+].O>[CH2:14]([O:13][P:12]([CH:2]([F:30])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)([O:16][CH2:17][CH3:18])=[O:19])[CH3:15]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)C(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
To a mixture of diethyl α-hydroxy-4-nitrobenzylphosphonate (1.0 g) and chloroform (10 mL) was added diethylaminosulfur trifluoride (1.4 mL) at −78° C. and the reaction mixture was warmed to room temperature. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated and the residue was purified by preparative HPLC to give 4-[(diethylphosphono)(fluoro)methyl]nitrobenzene (0.1 g, yield 10%) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21]C(=O)OCC5C=CC=CC=5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:21][C:18]12[CH2:17][CH2:16][CH:15]([CH2:20][CH2:19]1)[CH2:14][N:13]1[C:32](=[O:35])[C:33]([OH:34])=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=3)=[O:9])[N:11]=[C:12]21
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 72.8 %

Procedure:
To a mixture of benzyl (2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate (300 mg, 0.59 mmol) in methanol (3 mL) was added 10% Pd/C (315 mg) and the mixture was stirred under balloon hydrogen atmosphere for 18 h. The mixture was then filtered through a pad of CELITE® and the pad washed with ethyl acetate. The filtrate was concentrated to afford the title compound (160 mg, 72% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ: 12.22 (s, 1H), 9.50 (brs, 1H), 7.35-7.41 (m, 2H), 7.19-7.22 (m, 2H), 4.54 (d, 2H, J=5.8 Hz), 4.01 (s, 2H), 2.42-2.48 (m, 3H), 2.08 (s, 2H), 1.98-2.03 (m, 2H), 1.84-1.90 (m, 2H), 1.70-1.78 (m, 2H). LCMS (M+H)=373.28.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8]([Cl:11])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C1COCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:11][C:8]1[C:9]2[S:10][C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc(Br)sc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: N#Cc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc2ncnc(Cl)c2s1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-4-chloro-thieno[3,2-d]pyrimidine (10.0 mmol), (trimethylsilyl)acetylene (12.0 mmol), Pd(PhCN)2Cl2, (1.0 mmol), CuI (1.0 mmol) and TEA (2.0 mmol) in dry THF (60.0 mL) was flushed with dry N2 for several minutes and stirred at 60° C. for 30 minutes under an atmosphere of N2. The solvent was removed and the residue purified by flash column chromatography on silica gel to provide 4-chloro-6-trimethylsilanylethynyl-thieno[3,2-d]pyrimidine (compound 48.1) in 65% yield. EIMS (m/z): calcd. for C11H11ClN2SSi (M+)+H 266.01. found 266.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[C:37]([NH:40][CH2:41][CH2:42][NH2:43])(=[O:39])[CH3:38]>>[C:37]([NH:40][CH2:41][CH2:42][NH:43][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:39])[CH3:38]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CC(=O)NCCN
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCNC(C)=O)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with N-acetylethylendiamine.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:28][CH:29]([CH2:41][CH3:42])[C@@H:30]([C:32]1[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[O:34][N:33]=1)[OH:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:28][C@H:29]([CH:30]([OH:31])[C:32]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[O:34][N:33]=2)[CH2:41][CH3:42])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: CCC(N)[C@H](O)c1noc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1noc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A solution of (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (223 mg, 0.788 mmol) in dimethylformamide (10 ml) was treated successively with (S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoroacetic acid (267 mg, 0.788 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (299 mg, 0.787 mmol) and diisopropylethylarmine (0.274 ml, 1.576 mmol). Reaction stirred at room temperature overnight. Solvent evaporated under reduced pressure. Residue taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and water, dried over Na2SO4 and solvent evaporated under reduced pressure to give (R)-2-Cyclohexylmethyl-N-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide as a yellow solid (324 mg).