Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[P:30](Cl)(=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>CC(OC)(C)C>[CH2:32]([O:31][P:30]([O:1][C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O:34][CH2:35][CH3:36])=[O:37])[CH3:33]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CCOC(=O)C1=C(OP(=O)(OCC)OCC)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 1-tert-butyl 3-ethyl 4-oxopiperidine-1,3-dicarboxylate (11.50 g, 42.4 mmol, ASDI) in MTBE (500 mL) at about −78° C. was added NaHMDS (1 M in THF, 53.0 mL, 53.0 mmol). After about 1 h, diethyl phosphorochloridate (7.62 mL, 53.0 mmol) was added to the reaction mixture. After about 30 min, the reaction mixture was allowed to warm to ambient temperature and stirred for about 16 h. The reaction mixture was partitioned between saturated aqueous NH4Cl (100 mL) and EtOAc (50 mL). The layers were separated. The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to yield 1-tert-butyl 3-ethyl 4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (8.55 g, 49%) as a yellow oil: LC/MS (Table 1, Method b) Rt=2.35 min; MS m/z: 408 (M+H)+.
Reaction SMILES: C(O)C.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:30]CC2C=CC=CC=2)=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[O:13])(=[O:6])[CH3:5]>[C].[Pd].O1CCCC1>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:13])(=[O:6])[CH3:5]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Ethanol (6 mL) and tetrahydrofuran (72 mL) were added to 5-acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (602 mg, 1.25 mmol) and 5% palladium-carbon (60 mg), and the mixture was hydrogenated at room temperature for 30 minutes. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure and the residue was recrystallized from n-hexane-ethyl acetate to give the title compound (230 mg, 47.0%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][CH2:14][CH:15]([OH:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:7]=1[CH3:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[CH2:14][NH:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)[CH2:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[C:7]([CH3:22])[CH:8]=1)=[O:21]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(C(=O)NCC(O)C(C)(C)C)cc2C)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(C(=O)NCC(=O)C(C)(C)C)cc2C)cc1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a mixture of methyl 4-((4,4,4-trifluoro-1-(4-((2-hydroxy-3,3-dimethylbutyl)carbamoyl)-2-methylphenyl)butyl)amino)benzoate (479.1 mg) and ethyl acetate (10 mL) was added Dess-Martin Periodinane (616 mg) at room temperature, and the mixture was stirred overnight. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (433.8 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:25]([CH:33]=O)[NH:24][C:23]=2[CH3:35])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:25]([CH:33]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:35])=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCN1CCCC1
Yield: 27 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (44 mg, 0.21 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (70 mg, prepared in the same manner as the isopropyl analog, above) to give 0.03 g (27%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:8]2.[CH3:20][C:21]1[C:26](O)=[CH:25][CH:24]=[C:23]([CH3:28])[N:22]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:20][C:21]1[C:26]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:8]3)=[CH:25][CH:24]=[C:23]([CH3:28])[N:22]=1
Reactant: Cc1ccc(O)c(C)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCO)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCOc3ccc(C)nc3C)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
To a solution of ethyl [(1S)-5-(2-hydroxyethoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 249, 50.0 mg, 0.19 mmol) and 2,6-dimethylpyridin-3-ol (46.6 mg, 0.38 mmol) in THF (1.5 mL) were added PPh3 (99.2 mg, 0.38 mmol) and ADDP (95.5 mg, 0.38 mmol). The reaction mixture was vigorously stirred at rt for 24 h, and then directly applied to a silica gel column for purification (1:1 hexanes/EtOAc) to give the product (58.9 mg, 84%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H) 1.72-1.81 (m, 1H), 2.36-2.2.44 (m, 2H), 2.45 (s, 3H), 2.47 (s, 3H), 2.73 (dd, 1H) 2.82-2.92 (m, 2H), 3.52-3.56 (m, 1H) 4.19 (q, 2H), 4.26-4.33 (m, 4H), 6.75 (d, 1H), 6.82 (s, 1H) 6.92 (d, 1H), 7.05 (d, 1H), 7.08 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O>CC(O)=O.CCO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(F)ccc1Br

Procedure:
To a solution of 1-bromo-4-fluoro-2-nitrobenzene (5.0 g, 22.7 mmol) in HOAc/EtOH (20 mL/20 mL) was added iron powder in one portion at room temperature. The mixture was bubbled with N2 for 5 min, and then refluxed for 2 hrs. Partial of the solvents were removed on rotary vacuum, then the residue was partitioned between aqueous NaOH (10N, 200 mL) and Et2O (200 mL). After separation, the organic phase was washed with H2O (50 mL), brine (50 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product, as an light tan oil (quantitative yield), which was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 4.15 (s, 1H), 6.34 (td, J=8.44, 2.77 Hz, 1H), 6.46 (dd, J=10.20, 2.90 Hz, 1H), 7.31 (dd, J=8.81, 5.79 Hz, 1H); Mass spec. 189.94 (MH+), Calc. for C6H5BrFN 188.96.
Reaction SMILES: [CH3:1][CH2:2][OH:3].[K].Cl[C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1.Cl>O>[CH2:2]([O:3][C:6]1[C:7]([C:16]([F:17])([F:19])[F:18])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1)[CH3:1]
Reactant: CCO
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K]
Solvent: O
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Yield: 96 %

Procedure:
To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol), and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (57.74 g, 240 mmol) was added in one portion, and the resulting dark red mixture was stirred at 55-60° C. for 4 days. The warm reaction mixture was slowly poured into H2O (ca. 2000 mL), adjusted pH with conc. HCl to pH 2, the yellow precipitate was filtered off, washed with H2O and dried in air at 60° C. to give a yellow solid (57.81 g, 96%), which was used without further purification. MS (ISN) 249 [M−H].
Reaction SMILES: O=[CH:2][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:37][C@@H:38]2[O:43][C@@H:42](CO)[C@H:41](O)[C@@H:40](O)[C@@H:39]2[NH:48]C)[C@@]1(O)C=O>>[NH2:48][C@H:39]([C:38]([OH:37])=[O:43])[CH2:40][CH:41]([CH3:42])[CH3:2]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 2 h

Procedure:
pseudomesenteroides was cultivated in 10 ml M17 (0.5% glucose) for 3 days followed by cultivation for 120 minutes in the presence of 150 μl of EMS. After EMS treatment, 0.2 ml of the culture was inoculated into ten tubes each containing 10 ml of M17 and incubated for 3 days for phenotypic expression. The mutation frequency was monitored by plating 0.1 ml from each tube onto M17 plates containing 500 μg/ml of streptomycin.
Reaction SMILES: F[C:2]1([O:9][C:10]#[C:11][CH3:12])[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][CH2:3]1.[Br:13]C1C=CC(F)=CC=1O.BrC1C=C(F)C=CC=1OCC#C>>[Br:13][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:9][CH2:10][C:11]#[CH:12]
Reactant: CC#COC1(F)C=C(F)C=CC1
Reactant: Oc1cc(F)ccc1Br
Agent: C#CCOc1ccc(F)cc1Br
Product: C#CCOc1cc(F)ccc1Br
Yield: 87 %

Procedure:
This compound was prepared analogously to 2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-5-fluorphenol (15 g, 78 mmol) to give 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene 15.6 g (87%) 29f) 2-Bromo-4-fluoro-1-prop-2-ynyloxy-benzene
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O>O1CCCC1>[N:13]1([C:2]2[N:11]=[C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(N3CCCC3)nc(N3CCCC3)nc2c1

Procedure:
Ten grams of 2,4-dichloroquinazoline was added carefully to a solution of 25 ml of pyrrolidine in 200 ml of tetrahydrofuran. The resulting mixture was heated at reflux overnight and then was poured into a mixture of ice and water. The resulting mixture was extracted several times with ether. The ether extracts were combined and washed with water. The ether phase then was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a 1:1 benzene:hexane mixture to give 10.1 g of 2,4-bispyrrolidinylquinazoline; m.p. 127°-129°. The following analytical data were obtained:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.CON(C)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[N:21]=1)=[O:19].BrC1C=C(C(C2C3C(Cl)=NC=NC=3N(C(C)C)C=2)=O)C=NC=1>>[Br:26][C:22]1[N:21]=[C:20]([C:18]([C:2]2[C:10]3[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: CON(C)C(=O)c1cccc(Br)n1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Agent: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2c(Cl)ncnc21
Product: CC(C)n1cc(C(=O)c2cccc(Br)n2)c2c(Cl)ncnc21
Yield: 68.6 %

Procedure:
The title compound (34.0 g, 69%) was prepared from 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (35.8 g, 130.5 mmol) and 6-Bromo-pyridine-2-carboxylic acid methoxy-methyl-amide (32.0 g, 130.5 mmol) by procedures analogous to those described for the preparation (5-Bromo-pyridin-3-yl)-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone. MS: 380.6 (MH+); HPLC Rf: 6.05 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].[CH3:25][C:26]1([CH3:33])[O:30][C@H](CO)C[O:27]1>>[CH3:25][C:26]1([CH3:33])[O:30][C@H:2]([CH2:1][O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:3][O:27]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: C=CCOc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Product: COc1ccc2c(OC[C@@H]3COC(C)(C)O3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (R)-(−)-2,2,-dimethyl-1,3-dioxolane-4-methanol in place of allyl alcohol, the title compound was synthesized.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:16][CH2:17][S:18]([CH2:21][CH2:22]Br)(=[O:20])=[O:19]>CS(C)=O.C1COCC1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:22][CH2:21][S:18](=[O:20])(=[O:19])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=S(=O)(CCBr)CCBr
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 98.3 %

Procedure:
A slurry of NaH (71.4 mg, 1.79 mmol, 60% dispersion) in DMSO (3 mL) and THF (1 mL) was treated with solid (4-nitro-phenyl)-acetonitrile (121 mg, 0.744 mmol) and stirred at RT for 3 min. A solution of 1-bromo-2-(2-bromoethanesulfonyl)-ethane (250 mg, 0.893 mmol) in THF (3 mL) was added, and the mixture was heated to 70° C. for 1.5 h. The mixture was partitioned between EtOAc (100 mL) and water (75 mL), and brine (25 mL) was added. The aqueous layer was extracted with EtOAc (1×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column with 10-50% EtOAc-hexane afforded the title compound (205 mg, 98%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 8.33 (d, 2H, J=8.8 Hz), 7.75 (d, 2H, J=8.8 Hz), 3.64-3.52 (m, 2H), 3.29-3.19 (m, 2H), 2.88-2.76 (m, 2H), 2.54-2.44 (m, 2H).
Reaction SMILES: [C:1]([CH2:11][N:12]1[CH2:16][CH2:15][N:14]=[CH:13]1)([O:3]CC1C=CC=CC=1)=[O:2].C(O)C.[H][H].[ClH:22]>C(OCC)(=O)C.[Pd]>[ClH:22].[C:1]([CH2:11][N:12]1[CH2:16][CH2:15][N:14]=[CH:13]1)([OH:3])=[O:2]
Reactant: O=C(CN1C=NCC1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CN1C=NCC1

Procedure:
A suspension of 10.9 g. (0.05 mole) of N-carbobenzyloxymethylimidazoline and 50 mg. of 5% palladium-on-charcoal in 100 ml. of ethanol is shaken in an atmosphere of hydrogen at atmospheric pressure. When the theoretical amount of hydrogen has been absorbed, the spent catalyst is filtered and the filtrate treated with one equivalent of hydrogen chloride dissolved in ethyl acetate. The resulting solution is then concentrated to dryness in vacuo and the residual product triturated with ether and filtered.
Reaction SMILES: C(S([C:10]1[N:15]=[C:14]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:12][N:11]=1)(=O)=O)CCCCC.[NH2:31][CH:32]([CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH2:35]1)[CH3:33]>CS(C)=O>[CH2:43]([O:42][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][CH:34]([CH:32]([NH:31][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:33])[CH2:35]1)=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(N)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CCCCCCS(=O)(=O)c1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1
Solvent: CS(C)=O
Product: CC(Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)C1CCCN(C(=O)OCc2ccccc2)C1

Procedure:
The title compound was prepared from 2-hexanesulfonyl-4-[5-(pyridin-4-yl)-benzimidazol-1-yl]pyrimidine and 2-hexanesulfoxide-4-[5-(pyridin-4-yl)-benzimidazol-1-yl]pyrimidine 1:1 mixture and 3-(1-aminoethyl)-1-(benzyloxy-carbonyl)piperidine according to the procedure described in EXAMPLE 17 using DMSO instead of toluene as solvent. Mass spectrum (ESI) 534.4 (M+1)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]([C:19]2[CH:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:18])([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:25].[ClH:25].[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([NH:16][C:11]2([C:14]#[N:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:18])=[CH:20][N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(NC(=O)c2ccc(Cl)nc2)CCNCC1

Procedure:
A solution of 4-[(6-chloro-pyridine-3-carbonyl)-amino]-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.82 mmol) in 4 M HCl in dioxane (4 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. Note: The product is contaminated with some primary amide (partial hydrolysis of the nitrile). MS (ISP): 265.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>N1C=CC=CC=1>[CH2:1]([O:8][N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCCCCNOCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Temperature: 0 °C
Yield: 88.2 %

Procedure:
Pyridine (80 mL) was added to (7) (6.38 g, 20.7 mmol ) and succinic anhydride (3.11 g, 31.1 mmol ) and the reaction was heated under nitrogen at 80°-86° C. for 1.5 hours. Solvent was removed under high vacuum and the residue was dissolved with ether (150 mL) and washed with saturated NaHCO3 (4×50 mL). The aqueous portion was extracted with ether (2×50 mL), cooled to 0° C., acidified with cold 1N HCl (350 mL) and extracted with CHCl] (6×100 mL). A water wash (100 mL), solvent removal and flash column chromatography, eluting with 6% CH3OH/CH2Cl2, gave 7.46 g (88%) of (8) as a solid: mp 93°-94° C., NMR δ 1.2-1.8 (m+s, 16 H), 2.62 (s, 4 H), 2.9-3.2 (m, 2 H), 3.51-3.76 (m, 2 H), 4.8 (s, 2 H), 7.33 (s, 6 H). Anal. calcd. for C21H32N2O6 : C, 61.75; H, 7.90, N, 6.86. Found: C, 61.48; H, 7.90; N, 6.79.
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.[NH:19]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:20]1[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:19]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:20]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: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCCCN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl pipecolinate hydrochloride (Aldrich), the title compound was prepared as a solid (mp=114-118° C.). The reaction was monitored by tlc (Rf=0.71 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH2:21][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:30]=[CH:29][C:27]=1[OH:28]
Reactant: COc1cc(C=O)ccc1O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(CN2CCCC2)ccc1O
Yield: 74.6 %

Procedure:
NaB(OAc)3H (8.7 g, 0.041 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.4 mL, 0.041 mol) and vanillin (5 g, 0.033 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 2 h and cooled. Then 10 N NaOH (4.1 mL) and water (30 mL) were added. The organic layer was separated; the aqueous one was extracted with chloroform (2×50 mL). The organic fractions were evaporated. The residue was distributed between water and CH2Cl2. Concentrated HCl (2.98 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 6 and extracted with chloroform (2×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.1 g, 75%) was obtained as white crystals. 1H-NMR (400 MHz)-data (dmso-d6): 8.72 (s, 1H ArOH), 6.81-6.84 (m, 1H, Ar—H), 6.64-6.70 (m, 2H, Ar—H), 3.74 (s, 3H, ArOCH3), 3.43 (s, 2H, ArCH2), 2.36-2.41 (m, 4H, pyrrolidine (CH2)2N), 1.64-1.70 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][C:37](O)=[O:38]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:37](=[O:38])[CH2:36][O:35][CH2:34][CH2:33][O:32][CH3:31])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COCCOCC(=O)O
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: COCCOCC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-(2-methoxy-ethoxy)acetamide is prepared starting from trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 2-(2-methoxyethoxy)-acetic acid (Fluka, Buchs, Switzerland) according to a procedure known in the art (M. Bodanszky in Principles of Peptide Synthesis, Akad.-Verlag, 1984). Analytical HPLC: tR=6.91 min (Grad 2); ES-MS: m/eo=516.2.