Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:33]O)[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([NH2:28])=[N:26]O)=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>[C].[Pd].C(O)(=O)C>[NH2:33][C:2](=[NH:1])[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:28])=[NH:26])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: NC(=NO)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(=N)N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 61.2 %

Procedure:
To an acetic acid (10 mL) suspension of 1.07 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N′-hydroxybenzamidine was added 0.64 mL of acetic anhydride at room temperature, which was then stirred at room temperature for 40 minutes. To this mixture was added 0.10 g of 5% palladium-carbon, which was then stirred under hydrogen atmosphere for 2 hours and 15 minutes. Insoluble matter was filtered off before adding 4 mL of 6.0 mol/L hydrochloric acid, and insoluble matter was then filtered off, followed by distilling off the solvent under reduced pressure. A 5.0 mol/L sodium hydroxide aqueous solution was added to the resultant residue to adjust the pH to 12.5, followed by collecting the solid matter by filtration to provide 0.61 g of 4-{3-[4-(3-{4-[amino(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: [CH3:1][C:2]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][OH:35])[CH:27]=4)[CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][S:42]([O:35][CH2:34][CH2:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH2:13][CH2:12][CH2:11][N:10]4[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:36]=[CH:37][CH:38]=[C:39]([CH3:40])[C:2]=3[CH3:1])[CH:21]=[N:22]2)[CH:27]=1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCO)c5)c4)cccc32)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCOS(C)(=O)=O)c5)c4)cccc32)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 4-(2,3-dimethylphenoxy)-1-(5-(1-(3-(2-hydroxyethoxy)benzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one (0.07 g, 0.13 mmol) in CH2Cl2 (2 mL) at 0° C. was added methanesulfonyl chloride (0.019 g, 0.17 mmol) and triethylamine (0.029 mL, 0.21 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and then quenched with saturated NaHCO3. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated NaHCO3, and brine, dried and concentrated to afford the title compound (80 mg, 100%). LCMS, [M+H]+=618.4.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:15](O)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([N:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: CCCCCCCCNCC(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCN(CC(=O)OC)C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
Methyl 2-(octylamino)acetate (31.6 mg, 0.157 mmol) and n-octanoic acid (30.0 μL, 0.188 mmol) were dissolved in 1 mL of well-dried DCM under argon condition and EDC (90.3 mg, 0.471 mmol), HOBt (63.6 mg, 0.471 mmol) and DIPEA (135 μL, 0.785 mmol) were added. The reaction mixture was then stirred for 12 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 5 mL of water and the reaction mixture was extracted with DCM (4 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 44.7 mg (0.136 mmol, 87%) of the desired compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[N:12]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Benzyl chloroformate (Aldrich, cat #:119938) (191 mL, 1.34 mol) was slowly added to a cooled (at 0° C.) mixture of ethyl piperidine-3-carboxylate (Aldrich, cat #:194360) (200 g, 1.27 mol) and triethylamine (266 mL, 1.91 mol) in methylene chloride (1000 mL). The reaction mixture was allowed to gradually warm to ambient temperature and stirred for 3 h. The reaction was quenched by the addition of 1N HCl aq. solution and the product was extracted several times with methylene chloride. The combined extracts were washed with water, saturated aq. NaHCO3, water, brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as oil (359.8 g, 97%). LC/MS 292.2 (M+H)+.
Reaction SMILES: [C:1]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([OH:21])[C:15]([CH3:23])([CH3:22])[CH2:14]1)=[O:11].[CH3:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].OO.S([O-])([O-])=O.[Na+].[Na+]>O.C(O)(=O)C.C(#N)C>[C:1]([O:25][CH:26]1[CH2:27][C:28]([CH3:36])([CH3:35])[N:29]([O:34][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:30]([CH3:33])([CH3:32])[CH2:31]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:14][C:15]([CH3:22])([CH3:23])[N:16]([O:21][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:17]([CH3:19])([CH3:20])[CH2:18]1)=[O:11]
Reactant: CCCCCCCC
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 76 °C
Yield: 31 %

Procedure:
A solution of 0.308 g (1.14 g) of ferric chloride hexahydrate and 0.225 g (3.75 mmol) of glacial acetic acid in 5 ml of water is added to a mixture of 10.00 g (19.6 mmol) of bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 94 ml of acetonitrile, and 64 ml of n-octane that is heated to 76° C. The reaction mixture is kept at the reflux temperature of 76° as a solution of 11.52 g (169 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 3 hours. A solution of 0.106 g of ferric chloride hexahydrate and 0.102 g of glacial acetic acid in 1.6 g of water is added to the reaction mixture 1.75 hours after the peroxide addition is begun. A solution of 0.106 g of ferric chloride hexahydrate and 0.073 g of glacial acetic acid in 1.6 g of water is added to the reaction mixture 2.75 hours after the peroxide addition is begun. The reaction mixture is maintained at the reflux temperature for 1 hour after the peroxide is added. Excess peroxide is decomposed by stirring the reaction mixture with aqueous sodium sulfite solution. Solids are removed by filtration. The aqueous layer of the filtrate is extracted with ethyl acetate. The combined organic layers are concentrated, and the concentrate is purified twice by flash chromatography with a 100:7.5 mixture of heptane-ethyl acetate to afford 4.43 g (31% yield) of the title compound, a colorless liquid. NMR analysis shows a mixture of octyl regioisomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[K+]>>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:24]([F:29])([F:28])[C:23]([F:31])([F:30])[C:22]([F:33])([F:32])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Agent: [K+]
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc21
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccccc21

Procedure:
Using 2,2-bis(fluoromethyl)-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester and potassium heptafluorobutyrate, an oily product of 2,2-bis(fluoromethyl)-6-heptafluoropropyl-2H-1-benzopyran-4-carboxylic acid ethyl ester and an oily product of 2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylic acid ethyl ester were obtained according to the same method as in Example 23 (4). 2,2-Bis(fluoromethyl)-6-heptafluoropropyl-2H-1-benzopyran-4-carboxylic acid ethyl ester:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:53](=[O:54])[N:6]2[C:7]([C:40]([O:42]CC3C=CC([N+]([O-])=O)=CC=3)=[O:41])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([C:27]([O:29]CC6C=CC([N+]([O-])=O)=CC=6)=[O:28])[CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:55]([CH2:58][CH2:59][CH2:60]O)=[N+]=[N-]>>[NH2:55][CH2:58][CH2:59][CH2:60][N+:23]1[CH:24]=[C:25]([C:27]([OH:29])=[O:28])[CH:26]=[C:21]([C:19]([C:16]2[N:17]=[CH:18][N:13]3[CH:12]=[C:11]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:53](=[O:54])[N:6]5[C:7]=4[C:40]([O-:42])=[O:41])[S:15][C:14]=23)=[O:20])[CH:22]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(C(=O)OCc6ccc([N+](=O)[O-])cc6)c5)c4s3)[C@H](C)[C@H]12
Reactant: [N-]=[N+]=NCCCO
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cc(C(=O)O)c[n+](CCCN)c5)c4s3)[C@H](C)[C@H]12
Yield: 16.5 %

Procedure:
The title compound (11.5 mg) was prepared in the same manner as in steps a) and b) of Example 4, except that 97.2 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(4-nitrobenzyloxycarbonyl)pyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate and 27.0 mg of 3-azido-1-propanol were used as the starting compounds.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]3([OH:21])[C:13]4[C:18]([C:19](=[O:20])[C:10]3([OH:22])[C:9]=2[CH:23]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH3:4])([CH3:3])[CH3:2].[C:24]([OH:27])(=O)[CH3:25].N1C=CC=CC=1.C1C[O:37][CH2:36][CH2:35]1>>[C:36]([O:12][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:23][C:9]=1[C:10]1([O:22][C:24](=[O:27])[CH3:25])[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:21])(=[O:37])[CH3:35]
Reactant: CC(C)(C)c1ccc2c(c1)C1(O)C(=O)c3ccccc3C1(O)O2
Reactant: C1CCOC1
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)(C)C)cc1C1(OC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
8-tert-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.50 g, 1.6 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with anhydrous acetic acid (0.32 ml, 3.7 mmol), pyridine (0.13 ml, 1.8 mmol), and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.44 g, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>C(#N)C>[C:19]([NH:18][C:17](=[N:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[O:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)#[N:20]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cccc(N)c1
Solvent: CC#N
Product: COc1cccc(N=C(NC#N)Oc2ccccc2)c1

Procedure:
m-Anisidine (4.56 mL, 4.06 mmol, 1 eq.), and diphenylcyanocarbonimidate (967 mg, 4.06 mmol, 1 eq.) were mixed and refluxed in acetonitrile under N2 for 1 hour. Solids precipitated. The reaction was worked up by filtering off the solids. Obtained 580 mg as product. M.P.=170.0-171.0° C. NMR (300 MHz, DMSO-d6) δ 8.70-8.50 (m, 1H); 7.43 (t, 2H, J=7 Hz); 7.40-7.20 (m, 2H); 7.14 (d, 2H, J=7 Hz); 7.00-6.80 (m, 2H); 6.80-6.70 (m, 1H); 3.80 (s, 3H).
Reaction SMILES: C(O)C(O)C(O)C(O)C=O.[CH3:11][CH:12]([OH:21])[CH:13]([OH:20])[CH:14]([OH:19])[CH:15](O)[CH:16]=O.O=C[C@@H]([C@@H]([C@H]([C@H](C)O)O)O)O.C(O)(=O)C.N1CCCCC1>C(O)C>[CH3:16][CH:15]1[C:14](=[O:19])[C:13]([OH:20])=[C:12]([CH3:11])[O:21]1
Reactant: CC(O)C(O)C(O)C(O)C=O
Agent: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: O=CC(O)C(O)C(O)CO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1=C(O)C(=O)C(C)O1
Yield: 26 %

Procedure:
Several methods of preparation of these compounds involving a pentose or a 6-deoxyhexose are known: U.S. Pat. No. 2,936,308 (Hodge) discloses the reaction of L-rhamnose and piperidine acetate at 75°C. for 18 hours in ethanol and a 26% yield of 2,5-dimethyl-4-hydroxy-2,3-dihydrofuran-3-one was obtained according to Example 2. Although the desired compound was formed in a reasonable yield, it was contaminated with a nitrogen-containing by-product (2,5-dimethyl-4-piperidino-2,3-dihydrofuran3one), which was difficult to remove. The same preparation is disclosed in GB 1,132,600. GB 1,238,942 discloses the reaction between a pentose or 6-deoxy-aldohexose with a dialkylamine to a glycosylamine which further reacts with acid to form the desired compounds. Before isolating the product from the reaction mixture the solvent is removed by distillation under reduced pressure at a temperature below 35° C. The product is then isolated through extraction with an organic solvent followed by purification through column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19](O)=[O:20])=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]([NH:26][CH:23]4[CH2:25][CH2:24]4)=[O:20])=[C:14]([C:16]([NH2:17])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: NC1CC1
Reactant: NC(=O)c1nc2n(c1C(=O)O)C1CC(C1)c1ccc(Br)cc1-2
Product: NC(=O)c1nc2n(c1C(=O)NC1CC1)C1CC(C1)c1ccc(Br)cc1-2
Yield: 85 %

Procedure:
10-bromo-2-carbamoyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-3-carboxylic acid was reacted with cyclopropylamine similarly to as described in example 2 with non-critical modifications to afford 141 mg (85%) 10-bromo-N3-cyclopropyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. 10-bromo-N3-cyclopropyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 29 mg (18%) of N3-cyclopropyl-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]#[N:30])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[C:29]([C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:18]3[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:21][NH:22]2)=[CH:27][CH:26]=1)#[N:30]
Reactant: COC(=O)C(=O)c1c[nH]c2cc(C#N)ccc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(C#N)ccc45)C(=O)NC3=O)c21
Temperature: 70 °C

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.410 g, 2.18 mmol) and (6-cyano-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.480 g, 2.10 mmol) in DMF (30 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (7.6 mL, 7.6 mmol) dropwise over 5 minutes. The mixture was heated at 70° C. for 17 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated onto flash SiO2. Flash chromatography (60–70% EtOAc/hex) gave the title compound as a bright orange-red solid which was dried under vacuum at 75° C. overnight (0.416 g, 54%). 1H NMR (400 MHz, DMSO-d6) 12.29 (br s, 1H), 11.26 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.86 (br s, 1H), 7.63 (d, J=8 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 6.99 (dd, J=8, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 6.60 (d, J=8 Hz, 1H), 6.49 (d, J=3 Hz, 1H), 3.66 (s, 3H). IR (KBR, cm−1) 3282, 2223, 1751, 1698. MS (electrospray, m/z) 367.1 (M++1), 365.2 (M−−1). HRMS 367.1190 (M++1, calcd for C22H15N4O2 367.1195).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=3)[N:13]=[CH:12][N:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=3)[N:13]=[CH:12][N:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (112 mg) in THF (2.0 mL) and methanol (1.0 ml) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at 50° C. for 30 min. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (96 mg) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CSc1ccc(O)cc1
Reactant: O=C(NC1(CO)CCCC1)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ncc(F)cc2C(=O)NC2(CO)CCCC2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
2-Chloro-5-fluoro-N-(1-hydroxymethyl-1-cyclopentyl)-nicotinamide (100 mg, 0.367 mmol), 4-methylsulfanyl phenol (51 mg, 0.367 mmol) and caesium carbonate (131 mg, 0.403 mmol) were suspended in DMF (1.5 ml) and the reaction was heated to 50° C. and stirred at this temperature under nitrogen for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with brine (25 ml) followed by water (25 ml). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 95:5, by volume) to give 5-Fluoro-N-(1-hydroxymethyl-cyclopentyl)-2-(4-methylsulfanyl-phenoxy)-nicotinamide (27 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[CH3:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15](=[S:18])[CH2:16][Br:17]>>[BrH:17].[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:16][C:15]([C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=3[CH3:12])=[S:18])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1ccccc1C(=S)CBr
Reactant: Cc1[nH]c2ncccc2c1C
Product: Br
Product: Cc1ccccc1C(=S)Cn1cccc2c(C)c(C)nc1-2
Yield: 20.9 %

Procedure:
A solution of 0,2 g (1,4 mmol) 2,3-dimethylpyrrolo[2,3-b]pyridine and 0,34 g (1,4 mmol) o-methylthiophenacyl bromide was stirred at room temperature for 4 h. The precipitated product was filtred off and dried affording 0,11 g (20%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[Br:10][C:11]1[C:12]([O:22][CH3:23])=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH:19]=1)[C:16]([Cl:18])=[O:17]>O1CCCC1>[ClH:18].[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:16](=[O:17])[C:15]1[CH:19]=[C:11]([Br:10])[C:12]([O:22][CH3:23])=[CH:13][C:14]=1[O:20][CH3:21])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1cc(OC)c(C(=O)Cl)cc1Br
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(=O)NC2CN3CCC2CC3)cc1Br
Product: Cl
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A solution of 3-aminoquinuclidine (1.12 g, 0.0089 mole) in 20 ml tetrahydrofuran was added dropwise to a stirred solution of 5-bromo-2,4-dimethoxybenzoyl chloride (2.50 g, 0.0089 mole) in 100 ml tetrahydrofuran. The mixture was stirred at ambient temperature for 65 hr, and the solid was collected by filtration to yield 2.77 g. Recrystallization from methanol-isopropyl ether gave 1.45 g (40.2%), m.p. 240°-243° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:67])[C:55]4[C:59]([CH:60]=3)=[N:58][N:57](C3CCCCO3)[CH:56]=4)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:67][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccccc1
Reaction time: 0.08 h

Procedure:
Benzoic acid (10 mg, 0.08 mmol) in DMF (0.2 mL) was treated with HATU (27 mg, 0.07 mmol) in DMF (0.2 mL) and DIPEA (30 μL, 0.24 mmol). The reaction mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.2 mL). Reaction mixture was shaken for five minutes and left to stand at 22° C. for 18 hrs. Solvent was removed in vacuo and the product re-dissolved in methanol (1 mL) prior to application on to an SCX cartridge (1 g). Product was eluted after 1 hr with 2M ammonia in methanol (2×3 mL), fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method D) afforded the title compound.