Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1I)[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[C:1]([O:5][C:6](=[O:21])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[Cl:22])[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Product: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1). The product was purified by preparative HPLC (phenomenex gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). Light brown foam (67%). MS (ESI): m/z=411.11 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[C:14]([Si:18]([CH3:25])([CH3:24])[O:19][CH:20]1[CH2:23][NH:22][CH2:21]1)([CH3:17])([CH3:16])[CH3:15].CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.CO.O>[C:14]([Si:18]([CH3:25])([CH3:24])[O:19][CH:20]1[CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=2)[CH2:21]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(O[Si](C)(C)C(C)(C)C)C2)cc1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
A mixture of 3.0 g (12.4 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1), 2.3 g (12.4 mmol) 3-(tert-butyl-dimethyl-silanyloxy)-azetidine (US2008/214520A1), 4.9 g (97%, 49.6 mmol) NaOtBu, 1.48 g (4.96 mmol) 2-(di-tert-butylphosphino)biphenyl and 1.1 g (1.24 mmol) tris-(dibenzylideneacetone)-dipalladium(0) in 30 mL 1,4-dioxane is stirred for 45 min under microwave irradiation at 80° C. After cooling water and MeOH are added, the mixture is filtered, concentrated in vacuo and directly purified by HPLC (column: XbridgeC18; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=O)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:22][C:21](=[O:23])[CH3:24])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCC=O)ccc1OCc1ccccc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(CCC=CC(C)=O)ccc1OCc1ccccc1
Yield: 56.4 %

Procedure:
A solution of 2.3 g of 3-(p-benzyloxy-m-methoxyphenyl)propionaldehyde and 2.97 g of acetylmethylenetriphenylphosphorane in 22 ml of toluene was heated under reflux for 2 hours, toluene and then evaporated and the residue was purified by a chromatography using 30 g of silica gel and recrystallization from a mixture of ethyl ether and n-hexane (1:5) afforded 1.49 g of the desired compound melting at 59.5°-60.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[C:17](Cl)(=[O:19])[CH3:18].ClC1N=CC2C(C(=O)C)=CN(C3CCCC3)C=2N=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:17](=[O:19])[CH3:18])=[C:9]([CH3:11])[N:8]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[N:7]=1
Reactant: Cc1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(=O)Cl
Agent: CC(=O)c1cn(C2CCCC2)c2nc(Cl)ncc12
Product: CC(=O)c1c(C)n(C2CCCC2)c2nc(Cl)ncc12

Procedure:
1-(2-Chloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone is prepared from 2-Chloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine and acetyl chloride using a method similar to that for the preparation of 1-(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone given in Example 325.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH:17]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: Nc1cccnc1
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)Nc3cccnc3)ccc2N1
Yield: 37.4 %

Procedure:
A solution of 5-chlorosufonyl-2-oxindole (3 g) and 3-aminopyridine (1.46 g) in pyridine (15 mL) was stirred at room temperature overnight at which time a brown solid was present. The solid was filtered, washed with ethanol and dried under vacuum to yield 1.4 g (38%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)c1ccnc(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(CO)ccn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A solution of methyl 2-methyl-pyridine-4-carboxylate (800 mg, 6 mmol) in ether (5 ml) was added to lithium aluminium hydride (340 mg, 9mmol) in ether (10 ml) cooled to 5° C. and the mixture stirred for 2 hours. Water was added, the mixture was filtered through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-hydroxymethyl-2-methylpyridine (240 mg, 38%) as a yellow oil.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])(C)C)[CH3:12])(C)(C)C.C1(N)CCC1.[CH:36]([O:39][C:40]1[CH:41]=[C:42]([CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=1)C(N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CC1C=CC=CC=1)=O)([CH3:38])[CH3:37]>>[CH2:23]([C@H:8]([NH:7][C:6](=[O:30])[C:42]1[CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=[C:40]([O:39][CH:36]([CH3:38])[CH3:37])[CH:41]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH:15]1[CH2:16][CH2:17][CH2:20]1)[CH3:12])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Agent: NC1CCC1
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CCC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from cyclobutylamine and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([SH:13])[CH2:11][CH3:12].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15]>C1(C)C=CC=CC=1>[C:1]([S:13][CH2:10][CH2:11][CH3:12])(=[S:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCS
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCSC(=S)c1ccccc1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A mixture of benzoic acid (1.22 g), 1-propanethiol (0.76 g) and phosphorus pentasulfide (4.44 g) in toluene (40 ml) was refluxed for 10 h. A dark red color was developed immediately after heating. After the reaction was complete (as monitored by GC-MS), it was cooled to room temperature and purified by a column chromatography packed with neutral alumina, eluting with benzene. Removal of the solvent by distillation gave the single compound, propyl dithiobenzoate (1.21 g, 62%). It was further characterized by 1H and 13C-NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[CH2:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1)[CH3:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][CH3:18])=[CH:24][N:23]=1)[CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Reactant: CCc1ccc(CCl)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(COc2ccc3cc([N+](=O)[O-])cnc3c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
In DMF (9 mL) was dissolved 3-nitro-7-hydroxyquinoline (1.0 g, 5.28 mmol.). Sodium hydride (210 mg, 5.28 mmol.) and 5-ethyl-2-(chloromethyl)pyridine (818 mg, 5.28 mmol.) were added to the resulting solution under chilling with ice. The mixture was stirred overnight at room temperature. After the completion of reaction was confirmed, ethyl acetate and aqueous sodium sulfate were added. The ethyl acetate portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1), to give 710 mg of the desired compound as a yellowish white crystalline product (yield 44%).
Reaction SMILES: [N:1]1([C:6]2[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[N:31]#[C:32]Br>C(Cl)(Cl)Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:32]#[N:31])[CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:23][CH:24]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNCC2)n1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (1.00 g, 2.92 mmol) and potassium carbonate (1.5 g, 10.9 mmol) in chloroform (25 mL) was added cyanogen bromide (0.371 g, 3.5 mmol). The slung was refluxed for 48 hours then stirred at room temperature for an additional 48 hours. The reaction was filtered through a pad of celite, concentrated and chromatographed on silica gel (1:1 Hexanes/EtOAc) to afford the desired compound.
Reaction SMILES: [CH3:1][C:2]1OC([Si](C)(C)C)=[CH:4][C:3]=1C=O.C[Si](C)(C)C1OC=C(C=O)C=1.CI.[CH2:26]([Si:28]([CH2:38][CH3:39])([CH2:36][CH3:37])[C:29]1[O:30][CH:31]=[C:32]([CH:34]=[O:35])[CH:33]=1)[CH3:27].ICCCC>>[CH2:1]([C:31]1[O:30][C:29]([Si:28]([CH2:36][CH3:37])([CH2:26][CH3:27])[CH2:38][CH3:39])=[CH:33][C:32]=1[CH:34]=[O:35])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: Cc1oc([Si](C)(C)C)cc1C=O
Agent: C[Si](C)(C)c1cc(C=O)co1
Solvent: CCCCI
Solvent: CI
Product: CCCCc1oc([Si](CC)(CC)CC)cc1C=O

Procedure:
Using the same procedure as for 5-methyl-2-trimethylsilyl-4-furaldehyde but substituting 2-trimethylsilyl-4-furaldehyde (Compound 30) and methyl iodide with 2-triethylsilyl-4-furaldehyde (Compound 31) and 1-iodobutane, respectively, gives 5-butyl-2-triethylsilyl-4-furaldehyde (Compound 41). IR (neat): 1690 cm-1; 'HNMR (CDCl3):0.73 (q, 6H, J=8.4 Hz), 0.95 (m, 12H), 1.36 (p, 2H, J=7.5 Hz), 1.69 (p, 2H, J=7.5 Hz), 2.94 (t, 2H, J=7.5 Hz), 6.89 (s, 1H) and 9.91 (s, 1H) 13CNMR (CDCl3): 3.03, 7.17, 13.6, 22.2, 26.8, 30.4, 118.6, 122.5 158.4, 170.2 and 184.8. LRMS m/e (% abundance):266 (M+, 20) 238 (20) 237 (100), 87 (10) and 75 (20); HRMS exact mass calculated for C15H26O2Si 266.1702, found 266.1690.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=O)=[CH:2]1.[N:21]1(OC(N(C)C)=[N+](C)C)[C:25]2C=C[CH:28]=[CH:29][C:24]=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(N)CCC>>[CH2:25]([NH:21][C:12](=[O:14])[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[CH2:24][CH2:29][CH3:28]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCCCN
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenoic acid (100 mg, 0.3784 mmol.) in 2 ml of DMFd were added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoborate (121.5 mg, 0.3784 mmol.), N-hydroxybenzotriazole (51.1 mg, 0.3784 mmol) and N,N-diisopropylethylamine (129.2 μl, 0.7568 mmol). After stirring at room temperature for 30 min., 34.5 μl (0.3784 mmol.) of n-butylamine were added and the obtained solution was stirred at room temperature, for 24 hours. The resulting mixture was concentrated by evaporation of the solvent in vacuo, the residue was diluted with dichloromethane washed with 1 N NaOH, 1 N HCl, brine, dried over sodium sulphate and evaporated. The residual solid was triturated with Et2O to afford 49 mg of the title compound as a white solid (yield 41%) m.p. 177-179° C. (dec.)
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21](C(Cl)(Cl)Cl)[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1.[CH3:28][NH2:29]>CN(C)C=O.O>[CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[NH:22][C:21](=[N:29][CH3:28])[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1
Reactant: Cc1cc(CCCOc2c(C)cc(-c3noc(C(Cl)(Cl)Cl)n3)cc2C)on1
Reactant: CN
Solvent: O
Solvent: CN(C)C=O
Product: CN=c1[nH]c(-c2cc(C)c(OCCCc3cc(C)no3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
The product of Example 12 (1.00 g, 2.32 mmol) was added to 5 ml of 40% aqueous methylamine in dimethylformamide (3-5 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue (0.54 g) was purified by chromatography (Silica Gel 60, first with 2% methanol in methylene chloride and then with 50% ethyl acetate in hexanes) to give 300 mg (37.5%) of pure title compound as a yellow solid, mp 126.5°-127° C. (ethanol).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:11][C:12]1[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[I-:2].[CH2:3]([S:11][C:12]1[C:13]([C:17]2[CH2:18][N:19]([CH3:1])[CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCSc1nsnc1-c1cccnc1
Reactant: CI
Product: CCCCCCCCSc1nsnc1C1=CC=CN(C)C1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of 3-(4-octylthio-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)[S:5][C:6]=1[C:7]([OH:9])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:54][CH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CN(C=O)C>[O:58]1[CH2:59][CH2:60][CH:55]([NH:54][C:7]([C:6]2[S:5][C:4]([CH2:10][CH2:11][C:12]3[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:14][O:15][CH:16]=3)=[N:3][C:2]=2[CH3:1])=[O:9])[CH2:56][CH2:57]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)NC1CCOCC1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 4-methyl-2-[2-(3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (70 mg, 0.22 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (79 mg, 0.24 mmol), N,N-diisopropyl ethyl amine (190 μL, 1.11 mmol) and 4-aminotetrahydropyran (25 mg, 0.24 mmol). The resulting reaction mixture was stirred overnight and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 1:1) afforded the title compound (84 mg, 95%) as a white solid. S: m/e=399.2 [M+H]+.
Reaction SMILES: [CH2:1]([OH:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10](N(C(C)C)C(C)C)C.[CH2:19]([Si:37](C)(Cl)Cl)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C1(C)C=CC=CC=1>[CH3:10][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:19][SiH:37]1[O:9][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: CCCCCCCCCCCCCCCCCC[Si](C)(Cl)Cl
Reactant: OCc1ccccc1O
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC(C)C[SiH]1OCc2ccccc2O1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In a 1 l four-neck flask with stirrer, reflux condenser and dropping funnel, 31.7 g of salicyl alcohol (0.25 mol) and 66.7 g (0.52 mol) of dried N-ethyldiisopropylamine were suspended under argon in 100 ml of anhydrous toluene at 22° C. 110 g of Octadecylmethyldichlorosilane (95%; 0.25 mol) was melted and dissolved in 100 ml of dry toluene. This solution was added dropwise at 23 to 27° C. within 55 minutes, in the course of which an exothermic reaction was observed. Cooling with an ice bath held the reaction temperature at a maximum of 27° C. After the addition had ended, the temperature was raised to 40° C., and exothermicity (without heating to 45° C.) was again observed. The reaction vessel was then cooled to 40° C. with cold water, and it was stirred at this temperature for one hour and then cooled to RT. The suspension was left to stand at RT overnight. The precipitate (hydrochloride) was filtered off with suction through a P40 glass frit under N2, and the filtrate was concentrated by rotary evaporation at 120° C./5 mbar. Yield 80.9 g (77% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cccc(F)c1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-fluorophenyl)acetate hydrochloride (from Example D12 above), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.2 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:4]([C:13]([O:15]CC)=[O:14])[S:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[Br:1][C:2]1[C:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sc(N2CCOCC2)c(Br)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of ethyl 4-bromo-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylate (109 mg, 0.227 mmol) in THF (1.8 mL) and MeOH (0.37 mL) was added 1.00 M aqueous NaOH (1.82 mL, 1.82 mmol) and the resulting mixture was stirred at 45° C. overnight. The reaction was diluted with water (5 mL) and acidified to pH=3 with 1 N HCl. The mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried, filtered and concentrated in vacuo to give 92 mg (90% yield) of a white solid which was used as is in the next step. LC/MS (AA) ES+ 450, 452, 454. 1H NMR (400 MHz, DMSO-d6) δ: 13.21 (bs, 1H), 7.52 (d, 1H, J=8.0 Hz), 7.39 (d, 1H, 2.0 Hz), 7.09 (dd, 1H, J=8.0, 2.0 Hz), 4.36 (s, 2H), 3.74-3.71 (m, 4H), 3.13-3.11 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C([O-])(=O)C.[Na+].[Br:18]Br.C(Cl)Cl.CO>C(O)(=O)C>[Br:18][C:8]1[NH:7][C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=1
Reactant: BrBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reaction time: 3 h

Procedure:
100 g of 3-methyl-3,7-dihydropurine-2,6-dione and 49 g of sodium acetate are suspended in 800 ml of glacial acetic acid and heated to an internal temperature of 90° C., and 33.3 ml of bromine are slowly (approx. 3-4 hours) added. The suspension is the stirred at this temperature for 3 hours when, according to TLC (DCM/MeOH 10:1), the reaction is complete. The reaction solution is cooled and filtered with suction. The residue is washed with 100 ml of glacial acetic acid and 500 ml of water and dried in vacuo at 50° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29](Cl)(=[O:31])[CH3:30].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>CN(C)C=O.C(C(C)=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[C:29]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:31])[CH3:30]
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CC(=O)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 20 h
Yield: 25.9 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (6 g) in anhydrous dimethylformamide (70 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (0.8 g) in anhydrous dimethylformamide (20 cc) at a temperature close to 20° C. in the course of 10 minutes and agitation is continued for 1 and a half hours. Then, 1.4 g of acetyl chloride is added in the course of 10 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (70 cc) and extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (55 cc). A solution of oxalic acid (1.3 g) in methyl ethyl ketone (20 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 1.8 g of 3-acetoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 166° C.