Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:8]=[CH:13][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:7][CH2:6]1
Reactant: Cc1cccc(-c2cc(C)c(Br)c(C)c2)n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cccc(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-6-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=538 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[C:10](I)=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[F:21][C:22]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl.N1C=CC=CC=1>[C:3]([OH:19])(=[O:25])[CH3:4].[NH2:17][C:15]1[C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:25])[C:23]4[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[CH:30][C:22]=4[F:21])=[C:3]([O:19][CH3:20])[CH:4]=3)[N:9]=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COc1cc(-n2nc(I)c3ncnc(N)c32)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O
Product: COc1cc(-n2ncc3ncnc(N)c32)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
1-(4-Amino-3-methoxyphenyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (80 mg, 0.209 mmol) in dichloromethane (5 mL) and pyridine (0.5 mL) was cooled to 5° C. in an ice bath then 2-fluoro-4-(trifluoromethyl)benzoyl chloride (52 mg, 0.230 mmol) was added dropwise. The solution was warmed to ambient temperature for 30 minutes then the solvents were removed by evaporation. The residue was dissolved in methanol (10 mL), 10% palladium on carbon (50 mg) was added and the mixture was hydrogenated at atmospheric pressure and 60° C. for 1 hour. The catalyst was removed by filtration through a pad of diatomaceous earth then the filtrate was concentrated and the material purified by preparative reverse phase chromatography. Lyophilization yielded the title compound (25 mg) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.98 (s, 1H), 8.32 (m, 3H), 7.99 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.32 (d, 1H), 7.18 (m, 1H), 6.7 (bs, 2H), 3.93 (s, 3H), 1.60 (s, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 18.75 min; MS: MH+ 447.1, M−H+ 445.1
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][NH:33][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[O:32])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)CNC(=O)c1ccccn1
Product: Cl
Product: O=C(CNC(=O)c1ccccn1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and N-(pyridin-2-ylcarbonyl)glycine, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]([CH2:8]Cl)=[N:6][CH:7]=1.[C:22]([N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28][C:27]1=[O:35])([CH3:25])([CH3:24])[CH3:23].[Li]>C1COCC1>[C:22]([N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH:28]([CH2:8][C:5]2[C:4]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[C:27]1=[O:35])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)[Si](OCc1cc(Cl)cnc1CCl)(C(C)C)C(C)C
Reactant: CC(C)(C)N1C(=O)Cc2cccnc21
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1cc(Cl)cnc1CC1C(=O)N(C(C)(C)C)c2ncccc21)(C(C)C)C(C)C
Reaction time: 0.67 h

Procedure:
A solution of 65 (23.84 g, 60.7 mmol) and 54 (17.32 g, 91 mmol) in THF (200 ml) was degassed by vacuum/flush N2 below 5° C. To the solution was added lithium amoxide solution in heptanes (27.4 mL, 40%, 85 mmol) maintaining below 7° C. The reaction was aged below 5° C. for 40 min, then quenched with saturated aqueous NH4Cl (10 mL), diluted with hexane (120 mL). The organic layer was separated, washed with saturated aqueous NH4Cl (100 mL) and water (150 mL), concentrated and purified by silica gel column (0 to 5% AcOEt/hexane) to obtain 69, which was used in the next reaction without further purification. HRMS m/z calcd. for C28H41C1N3O2Si 502.2651 (M+H). found 502.2641
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[C:20](=[N:28]O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=3)=[N:28][C:20]=2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: NCc1ccc(CCO)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(CCO)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
4-(2-Hydroxyethyl)phenylmethylamine and tert-butyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate are dissolved in pyridine, and the mixture is treated in the same manner as in Starting Material Synthetic Example 170 to give the objective tert-butyl 5-(4-chlorophenyl)-2-[4-(2-hydroxyethyl)phenyl]imidazole-4-carboxylate.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C.Br[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[ClH:2].[Cl:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1ccc(N2CCN(CCCc3ccccc3)CC2)nn1
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of 3.6 parts of 3-chloro-6-(1-piperazinyl)pyridazine monohydrochloride, 5.3 parts of sodium carbonate and 90 parts of N,N-dimethylacetamide was stirred for a while at 60° C. Then there were added 3 parts of (3-bromopropyl)benzene and the whole was stirred overnight at 60° C. The reaction mixture was poured into water. The product was filtered off and converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 3.2 parts (60%) of 3-chloro-6-[4-(3-phenylpropyl)-1-piperazinyl]pyridazine monohydrochloride; mp. 207.3° C. (compound 226) In a similar manner there were also prepared:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].C(OC([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:42]CCl>>[ClH:42].[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:24]2[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]2)=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13].[ClH:42]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CSc1ccc(N)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CSc1ccc(NC2CCNCC2)cc1C(F)(F)F
Product: Cl
Reaction time: 48 h

Procedure:
4-Methylsulfanyl-3-trifluoromethyl-phenylamine (414 mg; 2.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (400 mg; 2.00 mmol) and sodium triacetoxyborohydride (1.27 g; 6.00 mmol) are suspended in dichloromethane (10 mL) and the resulting mixture is stirred for 2 days. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired intermediate. The crude intermediate is then dissolved in dichloromethane (5 mL) and trifluoroacetic acid is added (2.5 mL). After 90 minutes reaction time, the mixture is concentrated under reduced pressure and co-evaporated twice with dichloromethane (10 mL). The crude residue is then triturated with a 4N solution of hydrochloric acid in dioxane (5 mL) until a precipitate forms. The solid is filtered and dried under high vacuum to afford the desired product as hydrochloride (354 mg; 1.09 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:25][OH:26])=[N:21][CH:22]=[CH:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:25][C:20]2[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1cccnc1CO
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cccnc1COc1nc(N)nc(-n2cccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([CH3:26])[CH:28]=4)=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-methylbenzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.Cl>C(OC(=O)C)(=O)C.C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:5](/[CH:6]=[CH:20]/[C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=2)[CH:4]=1.[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[C:20](/[C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)\[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(/C=C(\C(=O)O)c2ccc(O)cc2)cc(OC)c1
Product: COc1cc(/C=C/c2ccc(O)cc2)cc(OC)c1
Temperature: 150 °C
Reaction time: 20 h

Procedure:
Pterostilbene was synthesized as previously described (Joseph et al., supra). Briefly, pterostilbene was synthesized by condensation of 3,5-dimethoxybenzaldehyde and 4-hydroxyphenylacetic acid in acetic anhydride and triethylamine. The reaction mixture was heated (150° C.) under an atmosphere of nitrogen and continuously stirred. After 20 h, the reaction was stopped and cooled to room temperature, and concentrated hydrochloric acid (5 mL) was added. A precipitate formed, and this was dissolved in 50 mL of chloroform and then extracted with 10% aqueous sodium hydroxide. The aqueous extract was acidified to pH 1 with concentrated hydrochloric acid and stirred for at least 6 h, resulting in the precipitation of the intermediate product, α-[(3,5-dimethoxyphenyl)methylene]-4-hydroxy-(αZ)-benzeneacetic acid. This intermediate product was heated with 1.0 g of copper in 10 mL of quinoline (200° C., 6 h, under nitrogen). The reaction mixture was cooled to room temperature and filtered. To the filtrate was added 5 N hydrochloric acid (25 mL), which Was stirred for 1 h and then extracted with chloroform. The chloroform extract containing impure pterostilbene was purified by flash chromatography on a Horizon HPFC system (Biotage, Inc., Charlottesville, Va.), using a silica gel column and the solvent system ethyl acetate:hexane (linear gradient from 15:85 to 100% ethyl acetate). Fractions containing pure pterostilbene were combined and concentrated in vacuum. Pterostilbene was recrystallized in hexane, and its structure was confirmed from its spectroscopic data (UV, mass spectrometry, and nuclear magnetic resonance spectroscopy) (FIG. 1).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[CH:7]SC=2)NC(=O)[C:3]=1[C:12]#[N:13].C(O[C:17]([C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:26]([C:27]=1[OH:28])=[CH:25][S:24][CH:23]=2)=[O:18])C.C1(N)CCCCC1>>[CH:12]1([NH:13][C:17]([C:19]2[C:20](=[O:29])[NH:21][C:22]3[C:26]([C:27]=2[OH:28])=[CH:25][S:24][CH:23]=3)=[O:18])[CH2:3][CH2:2][CH2:10][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1c(O)c2cscc2[nH]c1=O
Reactant: N#Cc1c(Cl)c2cscc2[nH]c1=O
Solvent: NC1CCCCC1
Product: O=C(NC1CCCCC1)c1c(O)c2cscc2[nH]c1=O

Procedure:
To prepare compounds of structure (II) with R2 as carbonitrile, and R1 and R3 as defined above, 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33), was used as a key intermediate. To prepare this intermediate, 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester, depicted by formula (23), was reacted with cyclohexylamine to yield intermediate 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid cyclohexylamide, depicted by formula (31). This intermediate was converted to 5,7-dichloro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (32), by reacting with phosphorous oxychloride, and was then converted into 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-6-carbonitrile, depicted by formula (33), as shown in Scheme 15.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[NH2:8].Cl.[CH3:19][O:20][CH2:21][C:22](=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25].C([O-])(=O)C.[Na+]>O.CO>[F:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:15])([F:16])[F:17])[CH:10]=[CH:9][C:7]=1[NH:8][N:1]=[C:23]([C:22](=[O:28])[CH2:21][O:20][CH3:19])[C:24]([O:26][CH3:27])=[O:25]
Reactant: Nc1ccc(OC(F)(F)F)cc1F
Reactant: COCC(=O)CC(=O)OC
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(=O)C(=NNc1ccc(OC(F)(F)F)cc1F)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
A solution of sodium nitrite (1.9 g, 28 mmol) in H2O (10 mL) was added dropwise to a solution of 2-fluoro-4-(trifluoromethoxy)aniline (4.6 g, 24 mmol) in 6 M HCl (24 mL, 144 mmol) at 0° C. After stirring for 15 min at 0° C.; the mixture was added to a suspension of methyl 4-methoxyacetoacetate (3.1 mL, 24 mmol) and sodium acetate (12 g, 144 mmol) in MeOH (50 mL) pre-cooled at 0° C. The formed precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound (4.8 g, 58% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.51 (3H, s), 3.94 (3H, s), 4.65 (2H, s), 7.06-7.14 (2H, m), 7.59-7.68 (1H, m), 12.98 (1H, brs).
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:13][C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[C:3]1=O.C([SiH](CC)CC)C.CO.C(Cl)Cl>C(O)(C(F)(F)F)=O>[F:15][C:2]1([F:1])[CH2:13][C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CC(F)(F)C2=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c([nH]1)CC(F)(F)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.7 %

Procedure:
To a solution of methyl 5,5-difluoro-4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (111.2 mg, 0.517 mmol) in TFA (1 mL) under nitrogen at 25° C. was added triethylsilane (0.25 mL, 1.55 mmol) and the reaction mixture was stirred for 18 h at 25° C. TLC analysis (10% MeOH/DCM) indicated that all starting material had been consumed. The solvent was removed using a nitrogen stream and the residue was taken up in MeCN and purified by reverse-phase chromatography (MeCN/H2O, 0.05% TFA) to afford 3.9 mg of methyl 5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate in 3.8% yield. 1H NMR (400 MHz, ACETONE-d6) δ ppm 3.15 (t, 2H), 3.31 (t, 2H), 3.76 (s, 3H), 6.64 (d, 1H), 10.83 (bs, 1H); 19F NMR (400 MHz, Acetone-d6) δ ppm −86.73; LCMS-MS (ESI+) 202.0 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[C:7]#[N:8])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2ccc(I)cc2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(I)cc2C#N)c1CN(C)C
Yield: 38 %

Procedure:
In analogy to example 5b, 5-iodo-2-(4-methyl-imidazol-1-yl)-benzonitrile (+regioisomer) was reacted with Eschenmoser's salt in DMF for 72 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a white solid (yield: 38%). MS: m/e=367.0 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[CH3:12].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CN(C=O)C>[CH2:11]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1)[CH3:12]
Reactant: CCc1ccc(N2CCNCC2)cc1
Reactant: O=C1CCCN1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(N2CCN(CCCN3CCCC3=O)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (2.0 g, 12.0 mmol), 1-(4-ethylphenyl)piperazine (2.36 g, 12.0 mmol), anhydrous Na2CO3 (0.658 g, 6.2 mmol) and NaI (0.18 g, 1.2 mmol) in dry DMF (10 ml) was stirred at 80° C. for 12 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHCl3 (2×30 ml). The extracts were dried over Na2So4 and concentrated under reduced pressure to give 1-[4-(4-ethylphenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 2.43 g (62.0%). IR (Neat): 2940, 2800, 1660, 1440, 1000, 900,800. 1H NMR (CDCl3): 1.20(t, 3H, J=6.0 Hz, CH2CH3, 1.60-280(m, 14H, 3',4',2,1 & 2×N--CH2, CH2CH3), 3.00-3.60(m, 8H, 5', 3 & 2×N--CH2). MS: m/z 315 (M+).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:7]3[N:8]=[CH:9][CH:10]=[C:11](O)[N:6]3[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+].C([O-])(O)=O.[Na+]>>[Cl:16][C:11]1[N:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:13]=[C:7]2[N:8]=[CH:9][CH:10]=1
Reactant: Oc1ccnc2cc(C3CC3)nn12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccnc2cc(C3CC3)nn12
Temperature: 100 °C

Procedure:
A mixture of 2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ol (0.400 g, 2.28 mmol) and phosphorous oxychloride (4.26 ml, 45.7 mmol) in a resealable tube was heated to 100° C. After 4 hrs the solution was cooled to RT and slowly poured onto ice. The mixture was made basic using 2 N NaOH and saturated NaHCO3 and extracted with EtOAc. The combined organic fractions were washed with brine and dried with sodium sulfate. The organic phase solution was passed over a plug of silica gel and concentrated in vacuo to afford 7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine as a brown oil that was advanced without further purification. MS: Found M+H+=194.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13]C1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:25](CC)CC)C.ClC(OCC)=O.[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37]>C(Cl)(Cl)Cl>[NH2:25][C@H:41]1[C@H:40]([O:39][C:36](=[O:38])[CH3:37])[NH:11][C:9]1=[O:8].[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:13]([O:39][C:36](=[O:38])[CH3:37])[NH:25][C:20]1=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1N
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: -2.5 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine (5.98 g, 20 mmol) and triethylamine (2.02 g, 20 mmol) in chloroform (100 ml), ethyl chloroformate (2.18 g, 20 mmol) was added at -15° C. The reaction mixture was stirred at a bath temperature of -10 to 5° C. for 1.5 hrs. Then a precooled (ca. -15° C.) solution of (3S,4S)-3-amino-4-acetoxy-azetidin-2-one in ethyl acetate, which was obtained from hydrogenation of (3S,4S)-3-benzyloxycarbonylamino-4-acetoxy-azetidin-2-one (see above), was added at -15° C. and stirring was continued at a bath temperature of -15 to 5° C. for 1 hr. After removal of solvent, the residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:2) as eluent and the title compound was obtained as white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH2:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COCc1ccccc1CN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COCc1ccccc1CNC(C)=O
Temperature: 60 °C

Procedure:
604 g (4 moles) of o-aminomethylbenzyl methyl ether were dissolved in 1,500 ml of toluene, and 408 g (4 moles) of acetic anhydride were added to the stirred and cooled solution at a rate such that 60° C. was not exceeded. Stirring was continued, the mixture was neutralized with 424 g of 25% strength sodium hydroxide solution, and the aqueous phase was separated off. When the organic phase was evaporated down, 656 g (85% of theory) of the acylated benzyl ether of melting point 67°-68° C. crystallized.