Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.Cl[Sn:13]([CH3:16])([CH3:15])[CH3:14]>C(OCC)C>[CH3:1][C:2]1[S:3][C:4]([Sn:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][N:6]=1
Reactant: Cc1nccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ncc([Sn](C)(C)C)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 2-methylthiazole (1.0 g, 10 mmol) in anhydrous diethyl ether (20 mL) under an atmosphere of nitrogen was added n-butyllithium (2.5M solution in hexanes, 5.2 mL, 13 mmol) dropwise over 10 minutes. The reaction mixture was stirred for 1 h and then allowed to warm to 0° C. and stirred for 1 h. The reaction mixture was then cooled to −78° C. and a solution of chlorotrimethylstannane (1.8 g, 9.0 mmol) in anhydrous diethyl ether (10 mL) was added dropwise over 10 minutes. The reaction mixture was stirred for 30 minutes and then allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as a yellow oil which was used without any further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([I:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:35]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1.C[O-].[Li+]>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:16])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(I)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 54.1 %

Procedure:
A mixture of 5.00 g of 2-butyl-6-iodo-4(1H)-quinazolinone, 16.98 g of 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 0.695 g of lithium methoxide in 60 ml of tetrahydrofuran is heated at reflux for 40 hours. The reaction mixture is cooled, filtered and concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:9 ethyl acetate-hexanes to 1:5 ethyl acetate-hexanes to give 6.638 g of the desired product as a solid. FAB mass spec. 805 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH3:41]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH3:41])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
General Procedure A. To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 40 mg, 0.092 mmol) in DMF (2.0 ml) was added K2CO3 (39 mg, 0.28 mmol) and iodoethane (22 μl, 0.28 mmol). The reaction was stirred at room temperature for 48 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([C:3](=[CH:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([OH:7])=[O:6])#[N:2].[H][H].C(N(CC)CC)C.C([C@@H](CC(C)C)CC(O)=O)#N>CO>[C:1]([CH:3]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([OH:7])=[O:6])#[N:2]
Reactant: [H][H]
Reactant: CC(C)C=C(C#N)CC(=O)O
Agent: CC(C)C[C@H](C#N)CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)CC(C#N)CC(=O)O
Reaction time: 16 h
Yield: 51 %

Procedure:
The above procedure was followed to react 250 mg (1.634 mmol) of 3-cyano-5-methylhex-3-enoic acid with hydrogen (50 psi) in the presence of 8 mg (0.01634 mmol) of [(S,S)-Et-BPE]Rh(COD)+BF4− and 0.023 mL (0.1634 mmol; 0.1 eq) of triethylamine in 5 mL of methanol at 24° C. for 40 hours. The reaction mixture was filtered, the solvent was removed by evaporation, and the product was shown by proton NMR to be 71% (S)-3-cyano-5-methylhexanoic acid with 84% e.e. for the S-enantiomer. C. The above procedure was repeated, except that no base was added to the reaction mixture. The product was shown by proton NMR to be 26%, (S)-3-cyano-5-methylhexanoic acid having 91% e.e. for the S-enantiomer. D. The above procedure was followed to react 200 mg (1.307 mmol) of 3-cyano-5-methylhex-3-enoic acid with hydrogen (50 psi, 100 hours) in the presence of 10 mg (0.01307 mmol) of [(S,S)-Et-DuPHOS]Rh(COD)+BF4−. The product was shown by proton NMR to be 82% (S)-3-cyano-5-methylhexanoic acid having 56% e.e. for the S-enantiomer. E. The procedure of Example 5D was repeated, except that 0.1 eq. (0.02 mL, 0.1307 mmol) of triethylamine was added to the reactive mixture. The reaction was stopped after 16 hours, and the product was shown to be 86% (S)-3-cyano-5-methylhexanoic acid with 68% e.e. for the S-enantiomer. F. The procedure of Example 5E was repeated, except that 1 eq. (0.18 mL, 1.307 mmol) of triethylamine was added to the reaction mixture, and the reaction was stopped at 16 hours. The product was shown by proton NMR to be 92% converted to (S)-3-cyano-5-methylhexanoic acid having 56% e.e. for the S-enantiomer. G. By following the general procedures from above, 250 mg (1.634 mmol) of 3-cyano-5-methylhex-3-enoic acid was reacted with hydrogen (50 psi, 16 hours. 24° C.) in the presence of 12 mg (0.01634 mmol) of [(R,R)-DIPAMP]Rh(COD)+BF4− in methanol (10 mL) to provide 51% of 3-cyano-5-methylhexanoic acid having 72% e.e. for the R-enantiomer.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[OH:28][CH2:29][CH2:30][NH:31][NH2:32]>CO.ClCCl>[OH:28][CH2:29][CH2:30][NH:31][N:32]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:6][CH2:7]1
Reactant: NNCCO
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Solvent: ClCCl
Solvent: CO
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC(=NNCCO)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5 ml), 2-hydroxyethylhydrazine (29 mg, 0.37 mmol) added, and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 1.5% MeOH in dichloromethane. Relevant fractions were combined to give the desired product (98 mg). MS (ESP): 434 (MH+) for C20H24FN5O5.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=1[CH3:14].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>>[Br:3][C:4]1[N:8]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=1[CH3:14]
Reactant: CCOC(=O)c1c[nH]c(Br)c1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c(Br)c1C
Yield: 85.5 %

Procedure:
Using sodium hydride (60% in oil, 620 mg), ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (3.0 g) and tosyl chloride (2.95 g), a procedure as in Reference Example 41 was performed to give the title compound as pale-yellow crystals (yield 4.27 g, 86%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[CH3:29])=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[C:26]([O:28][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:25]=[CH:24][C:23]=1[CH3:29])=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (1.26 g, 8.92 mmol) and 3-(1-cyano-1-methylethyl)-N-(5-hydroxy-2-methylphenyl)benzamide (2.50 g, 8.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.85 g, 13.3 mmol) and the mixture was stirred at 60° C. for 4 hr, and further at 70° C. for 12 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 ml), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL) successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.41 g, 97%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=1[F:21])#[CH:2].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][N:24]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]#[C:1][C:3]2[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=2[F:21])=[N:24][CH:25]=1)[CH3:31]
Reactant: CCOc1ccc(Br)nc1
Reactant: C#Cc1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1ccc(C#Cc2ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc2F)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Under nitrogen, a mixture of tert-butyl [(1S)-2-(4-ethynyl-3-fluorophenoxy)-1-methylethyl]carbamate (9.36 g), 2-bromo-5-ethoxypyridine (5.86 g), bis(triphenylphosphine)palladium(II) dichloride (2.04 g), cuprous iodide (0.552 g), triethylamine (6.06 mL), and toluene (20 mL) was stirred at 100° C. overnight. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.00 g) as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(C)=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A solution of 4-mercaptophenol in dry acetone was treated successively with excess of potassium carbonate and ethyl bromoacetate. The reaction mixture was refluxed overnight. After allowing the reaction mixture to cool to rt, it was filtered through celite and washed with acetone. The filtrate was concentrated and the residue was partitioned between water and EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated in-vacuo. The residue was purified by flash chromatography (silica, hexanes:ether, 3:1 to 1:1) to provide the desired thioether.
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:27])[C@H:12]([C@@H:24]([CH3:26])[OH:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:28]([N:35]([CH3:49])[C@H:36]([C:46](O)=[O:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1CCC(N=C=NC2CCCCC2)CC1.NC(N)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:10][C:11](=[O:27])[C@H:12]([C@@H:24]([CH3:26])[O:25][C:46](=[O:47])[C@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[N:35]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH3:49])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C)cc1
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: NC(N)=O
Solvent: ClCCl
Product: COc1ccc(C[C@@H](C(=O)O[C@H](C)[C@H](NC(=O)OCc2ccccc2)C(=O)OCC(=O)c2ccccc2)N(C)C(=O)OC(C)(C)C)cc1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
2.00 g (5.38 mmol) of (8), 1.67 g (5.4 mmol) of (9) and 70 mg (0.54 mmol) of DMAP were dissolved in 20 ml of CH2Cl2 and cooled to -30° C., and 1.13 g (5.5 mmol) of DCC were added. The mixture .was allowed to reach RT overnight, the urea was filered off, the filtrate was concentrated, the residue was taken up in ether and left to stand for 1 h, and the urea was again filtered off. Sufficiently pure peptolide (10) was obtained by filtration through silica gel with PE/EA 7/3. Yield: 3.5 g (5.28 mmol, 98%), α!D20 =28.7° (c=0.96, CHCl3)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]C(=O)N(C)C)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].[OH-].[K+].C(O)C.Cl>O>[OH:19][C:5]1[C:6]([CH2:16][CH2:17][CH3:18])=[C:7]([SH:10])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(S)ccc(C(C)=O)c1O
Yield: 94.1 %

Procedure:
Reflux a stirred mixture of dimethyl-thiocarbamic acid S-(4-acetyl-3-hydroxy-2-propyl-phenyl) ester (1.08 g, 3.84 mmol), potassium hydroxide (1.1 g, 19.2 mmol), ethanol (25 mL), and water (10 mL) for 2 hours. Cool the reaction in an ice/water bath and adjust the pH to 2 with aqueous 5N hydrochloric acid. Extract the mixture with ethyl acetate (3×50 mL). Combine the extracts and wash with water (50 mL) and brine (50 mL) and dry over magnesium sulfate, filter, and concentrate to afford the title compound (0.76 g, 94%) as a brown oil which solidifies on standing. LCMS (m/z) 211 M−1.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][C:15](O)=[S:16])=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]1[CH2:28][CH2:27][N:26]2[C:21](=NC[CH2:24][CH2:25]2)[CH2:20][CH2:19]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:25]([N:26]([CH:21]1[CH2:20][CH2:19][CH2:18][CH2:28][CH2:27]1)[C:15](=[S:16])[CH2:14][CH2:13][CH2:12][C:11]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=[N:9][N:10]=1)[CH3:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: OC(=S)CCCc1nnnn1C1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)CCCc1nnnn1C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-(1-Cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml) and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is distilled off and the resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 47%), colorless liquid, nD18 =1.5290.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=O)[O:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1.N1CCCN2CCCN=C12>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:6]=[C:5]([C:7]([N:12]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)=[O:22])[CH2:19][CH2:20]2)[CH3:11])=[O:9])[O:4][N:3]=1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: COC(=O)c1cc(O)no1
Agent: C1CN=C2NCCCN2C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1cc(O)no1

Procedure:
A solution comprising of methyl 3-hydroxyisoxazole-5-carboxylate (20.72 mg, 0.145 mmol), 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (step 3) (50 mg, 0.145 mmol) and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (20.16 mg, 0.145 mmol) in DMF (483 μl) was refluxed for 18 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.O=P(Cl)(Cl)Cl.CN([CH:23]=[O:24])C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:23]=[O:24])=[C:4]2[N:3]=1
Reactant: CN(C)C=O
Reactant: Clc1cc(NC2CC2)n2nccc2n1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-chloro-N-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (156 mg, 0.75 mmol) in DMF was added POCl3 (205 μl, 2.25 mmol). The mixture was stirred at room temperature for 3 hours. Ice was added to quench excess POCl3 then the mixture was neutralized with 1M NaOH. DCM was added and the product was extracted three times. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. Some residual DMF could not be removed. LCMS (M+1=237)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[OH:24].IC.[C:28]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[O:24][CH3:28]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoic acid methyl ester (10 g, 28 mmol) from Step 1 was dissolved in DMF (100 mL) and cooled to 0° C. To the stirred solution was added iodomethane (6.1 g, 43 mmol) and Cs2CO3 (10 g, 31 mmol). The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 12 h. The solids were removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 20-40% EtOAc-hexane. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester was obtained as an oil.
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([OH:18])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3][CH3:4])=[O:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3][CH3:4])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ncc(O)c2c1[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ncc(OS(=O)(=O)c2ccc(C)cc2)c2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
In 10 ml of dioxane were dissolved 24.2 mg of the product of Example 2, followed by addition of 19.0 mg of p-toluenesulfonyl chloride and 10 mg of sodium carbonate. The mixture was stirred at room temperature for 4 hours and the resultant crystals were recovered by filtration and recrystallized from methanol to yield 35 mg of the title compound as colorless needles, m.p. 230°-231° C. Yield 89.7%.
Reaction SMILES: C([N:5]([C:13]1[C:17]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[CH:16][NH:15][C:14]=1[C:24]([O:26]C)=O)[C:6]([NH:8]C(OC)=O)=[NH:7])(OC)=O.C[O-].[Na+]>CO>[NH2:7][C:6]1[NH:8][C:24](=[O:26])[C:14]2[NH:15][CH:16]=[C:17]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:13]=2[N:5]=1
Reactant: COC(=O)NC(=N)N(C(=O)OC)c1c(Cc2ccsc2)c[nH]c1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(Cc3ccsc3)c[nH]c2c(=O)[nH]1
Yield: 85 %

Procedure:
Methyl 3-(N,N'-bis-carbomethoxyguanidinyl)-4-(3-thienylmethyl)-1H-pyrrole-2-carboxylate, obtained from Example 23 (3.94 g, 0.01 mol), sodium methoxide (1.62 g, 0.03 mol) and methanol (100 mL) were stirred together and boiled under reflux for six hours. The solvent was evaporated in vacuo and the residue was treated with water (200 mL) containing acetic acid (10 mL). The solid was collected by filtration and crystallized from ethanol to give 2.1 g (85%) of 2-amino-7-(3-thienylmethyl)-4-oxo-3H,5H-pyrrolo[3,2-d]pyrimidine as pale-yellow needles, mp 222°-224° C. with gas evolution, followed by resolidification and remelting at 268°-270° C. (lit.1 271°-272° C.).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([F:24])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1>O1CCOCC1.C(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:24])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Nc1ncnc2cc(F)c([N+](=O)[O-])cc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 74 ml of (R)-1-phenyl-ethylamine in 100 ml of dioxane is added dropwise to 108.8 g of 4-chloro-6-nitro-7-fluoro-quinazoline in 800 ml of methylene chloride while cooling with an ice bath. The reaction mixture is stirred overnight at ambient temperature. For working up it is extracted with water. The organic phase is dried over magnesium sulphate and evaporated down. The residue is purified by chromatography through a silica gel column with petroleum ether/ethyl acetate (1:1) as eluant.