Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([OH:10])=[O:9])[C:4]([SH:7])([CH3:6])[CH3:5].[CH3:11][C:12]([CH3:14])=O>>[CH3:5][C:4]1([CH3:6])[S:7][C:12]([CH3:14])([CH3:11])[NH:2][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: CC(C)=O
Reactant: CC(C)(S)C(N)C(=O)O
Agent: Cl
Product: CC1(C)NC(C(=O)O)C(C)(C)S1

Procedure:
Ninety-three grams (0.5 mole) of D,L-penicillamine hydrochloride in 500 ml of acetone were heated at reflux temperature for 30 minutes under a nitrogen atmosphere. After distilling off the excess acetone there were obtained 113 grams of D,L-2,2,5,5-tetramethyl-thiazolidine-4-carboxylic acid. The yield amounts to 99%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH:31](B3OC(C)(C)C(C)(C)O3)[CH:30]2[Si:41]([CH3:44])([CH3:43])[CH3:42])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH:30]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:31]2[C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH2:17]5)[N:13]([CH3:19])[C:12]=4[CH:20]=3)[C:4](=[O:21])[CH:3]=2)=[CH:27][CH:28]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Reactant: CC1(C)OB(C2C(c3ccc(Cl)cc3)C2[Si](C)(C)C)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(C4C(c5ccc(Cl)cc5)C4[Si](C)(C)C)cc3=O)cc21
Temperature: 70 °C
Yield: 17 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (108 mg), ((2RS,3SR)-2-(4-chlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)(trimethyl)silane (110 mg), potassium carbonate (130 mg), PdCl2(dppf) (11.5 mg), THF (6 ml) and water (2.0 ml) was heated at 70° C. overnight. The mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (26.0 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=[C:21]2I)=[CH:16][CH:15]=1.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:21]1[N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1
Reactant: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Reactant: OCc1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(OCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-6-fluorophenyl)methanol (160.5 mg, 0.99 mmol) in THF (8 mL) was added sodium hydride (40 mg, 0.99 mmol) and the reaction was stirred at room temperature. After 25 minutes ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (300 mg, 0.83 mmol) was added and the reaction was refluxed overnight. Water was added slowly and the solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 2-((2-chloro-6-fluorobenzyl)oxy)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (39).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[F:24][CH:25]([F:36])[CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(O)C>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH:14][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH2:26][CH:25]([F:24])[F:36])[CH:29]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(OCC(F)F)c1
Reactant: NCCc1c[nH]c2cc(Cl)ccc12
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)COc1cccc(CNCCc2c[nH]c3cc(Cl)ccc23)c1
Temperature: 78 °C
Reaction time: 8 h

Procedure:
Combine 2-(6-chloro-1H-indol-3-yl)ethylamine hydrochloride (1.0 g, 4.3 mmol) and ethyldiisopropylamine (900 μL, 5.2 mmol) in ethanol (150 mL) and stir at room temperature and treat with 3-(2,2-difluoroethoxy)benzaldehyde (856 mg, 4.6 mmol) and anhydrous sodium sulfate (12 g) and heat at 78° C. overnight. Cool to room temperature and filter. Treat the resulting filtrate with sodium borohydride (488 mg, 12.9 mmol) and stir the milky-white mixture at room temperature overnight. Remove in vacuo the solvent, and purification of the crude on silica gel eluting with 10% methanol in dichloromethane gives the free base of the title compound as a light yellow oil. Dissolve a portion of the oil (651 mg, 1.78 mmol) in methanol (15 mL) and treat with a homogenous solution of ammonium chloride (95 mg, 1.78 mmol) in methanol (3 mL). Sonicate the resulting solution for 10 minutes before removal of the solvent in vacuo to provide an off-white solid. Triturate with diethyl ether containing a few drops of acetonitrile. Filtration and drying of the precipitate afforded the title hydrochloride as a white solid: mp 131.6–133° C.; 1H NMR (400 MHz, dmso-d6): 11.15 (br s, 1H), 9.50 (br s, 2H), 7.57 (d, 1H, J=8.8 Hz), 7.39 (d, 1H, J=2.0 Hz), 7.36 (t, 1H, J=8.2 Hz), 7.32 (br s, 1H), 7.26 (d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=7.6 Hz), 7.04 (dd, 1H, J=7.8, 2.2 Hz), 7.01 (dd, 1H, J=8.4, 2.0 Hz), 6.41 (tt, 1H, J=54.4, 3.4 Hz), 4.32 (td, 2H, J=14.8, 3.6 Hz), 4.14 (br s, 2H), 3.11 (br s, 4H); MS (ES+): m/e 365.3 (M+1); CHN (for C19H19F2ClN2O.HCl.0.3H2O) calcd: C 56.11; H 5.11; N 6.89; found: C 56.03; H 4.95; N 7.18.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC.[Cl-].[Li+]>C1(C)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH:9]([C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)=[CH2:10]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Nc1ccc(Br)cn1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(N)nc1
Yield: 57.4 %

Procedure:
5-Bromopyridine-2-amine (2.51 g) was dissolved in toluene (150 mL), tributylvinyl tin (10.0 g), lithium chloride (1.23 g) and 2,6-di-tert-butyl-4-methylphenol (160 mg) were added and the mixture was heated under reflux for 2 hr 30 min. The resulting solid was removed by filtration, and the solvent was evaporated. The residue was dissolved in ethyl acetate and the insoluble material was removed again by filtration. The filtrate was extracted with 0.2 mol/L hydrochloric acid (100 mL, 50 mL), and the obtained hydrochloric acid solution was basified (pH 12) with 1 mol/L sodium hydroxide, extracted with ethyl acetate (200 mL), and the organic layer was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 5-vinylpyridine-2-amine (1.00 g). This was dissolved in ethyl acetate (80 mL). Under a nitrogen atmosphere, 10% palladium-carbon (330 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 8 hr. The reaction container was substituted with nitrogen (gas) and 10%-palladium carbon (300 mg) was added. The mixture was stirred under a hydrogen atmosphere for 4 hr. The reaction container was substituted with nitrogen (gas) and the catalyst was filtered off. The solvent was evaporated and the residue was dissolved in 0.4 mol/L hydrochloric acid (20 mL). The obtained hydrochloric acid solution was washed with ethyl acetate, basified (pH 12) with 1 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (773 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:29])([C:24]1[O:25][CH:26]=[CH:27][N:28]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[O:25][CH:26]=[CH:27][N:28]=1)[CH3:29]
Reactant: CC(C)(N)c1ncco1
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C2CCOCC2)c(OCC2CC2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=386.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](O)[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N(C(OC(C)C)=O)NC(OC(C)C)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:13][CH2:12][C@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: Oc1cncc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC(C)OC(=O)NNC(=O)OC(C)C
Agent: N#N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cncc(Br)c1
Yield: 56 %

Procedure:
[1-(tert-Butoxycarbonyl)-2(R)-azetidinyl]methanol (1.42 g, 7.60 mmol) was dried by azeotropic evaporation with toluene (3×10 mL) in a 50 mL round-bottom flask. 3-Bromo-5-hydroxypyridine (1.32 g, 7.60 mmol) and triphenylphosphine (2.20 g, 8.40 mmol, 1.1 equiv.) were added. The flask was capped with a rubber septum, and the atmosphere was exchanged three times with N2 (balloon). Anhydrous THF (25 mL) was added via syringe, and the mixture was stirred in an ice bath until all reagents were dissolved. Diisopropyl azodicarboxylate (DIAD, 1.76 mL, 8.40 mmol, 1.1 equiv.) was added dropwise in several portions over 30 min. The resulting mixture was stirred in the thawing ice bath overnight. After removal of the THF, the residue was purified by CC on SiO2 (25×3.8 cm, EtOAc/hexanes 1:4 to 3:7) to give crude product. A 1H NMR spectrum showed that the material was a mixture with diisopropyl hydrazodicarboxylate (containing approx. 56% of the title compound by mass), which was used directly for the next step. 1H NMR (CDCl3, 400 MHz; signals of the title compound only) δ 8.29 (d, 1H, J=1.8 Hz), 8.28 (d, 1H, J=2.7 Hz), 7.43 (t, 1H, J=2.3 Hz), 4.55-4.47 (m, 1H), 4.33 (br s, 1H), 4.13-4.09 (m, 1H), 3.93-3.85 (m, 2H), 2.40-2.20 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C@@H:7]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[ClH:34]>CCOCC.O>[ClH:34].[ClH:34].[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C@@H:7]3[CH2:24][NH:25][CH2:26][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCOc1cccnc1)C2=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCc1cc(C)c2c(c1)[C@@H]1CNC[C@H]1N(CCOc1cccnc1)C2=O
Reaction time: 0.08 h
Yield: 44 %

Procedure:
To a solution of (±)-trans tert-butyl 8-ethyl-6-methyl-5-oxo-4-(2-(pyridin-3-yloxy)ethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate (20 mg, 0.044 mmol) in 4 mL of ether was added 1 mL of 12 N HCl. The reaction was stirred vigorously for 5 min and then was diluted with 5 mL of water. The reaction was washed with ethyl acetate twice to remove the triphenylphosphine impurity. The aqueous layer was concentrated in vacuo, taken up in water, filtered and lyophilized to afford 8 mg (44%) of the title compound of Example 89 as a light tan powder. 1H NMR (DMSO-D6): δ 9.96-9.90 (broad m, 3H), 8.71 (s, 1H), 8.31-8.26 (m, 1H), 8.03-7.98 (m, 1H), 7.69-7.63 (m, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 4.28-4.23 (m, 1H), 4.20-4.15 (m, 1H), 4.07-4.00 (m, 1H), 3.90-3.84 3.82-3.70 (overlapping m, 2H), 3.55-3.49 (m, 1H), 3.46-3.39 (m, 1H), 3.33-3.26 (m, 1H), 3.21-3.14 (m, 1H), 2.50 (q, 2H, J=7.5 Hz), 2.46 (s, 3H), 1.08 (t, 3H, J=7.7 Hz). LRMS (ESI): 352.1 (M+H)+.
Reaction SMILES: OO.[NH2:3][C:4]1([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:8][CH2:7][N:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([NH2:17])[N:12]=[CH:11][N:10]=2)[CH2:5]1.C(=O)([O-])[O-:31].[K+].[K+]>CS(C)=O>[NH2:17][C:13]1[C:14]([C:15]([NH2:16])=[O:31])=[C:9]([N:6]2[CH2:7][CH2:8][C:4]([NH2:3])([CH2:18][NH:19][C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH2:5]2)[N:10]=[CH:11][N:12]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(N)ncnc1N1CCC(N)(CNC(=O)c2ccc(F)cc2F)C1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c(N)ncnc1N1CCC(N)(CNC(=O)c2ccc(F)cc2F)C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Hydrogen peroxide (0.38 ml; 4.29 mmol; 40.0 eq.) was added dropwise to the mixture of N-{[3-amino-1-(6-amino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl]methyl}-2,4-difluorobenzamide (40.0 mg; 0.11 mmol; 1.0 eq.) and potassium carbonate (118.45 mg; 0.86 mmol; 8.0 eq.) in DMSO (3.0 ml) at room temperature. The resulting mixture was then stirred at 40° C. for 2 hours. The reaction mixture was workup and the crude was purified by reverse phase chromatography (Yamazen, acetonitrile/0.1% NH4OH in water) to yield the title compound in 40% yield. LC-MS: (M+1=392, obsd.=392).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:14].[Li+]>C1COCC1.O>[C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:11]([OH:12])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 5-tert-butyl-2-methylfuran-3-carbonyl chloride (0.341 g, 1.699 mmol) in THF (2 ml) added lithium hydroxide (0.107 g, 2.55 mmol) in water (1 mL) and the mixture was stirred for 2 h at RT. Solvent was removed in vacuo and the residue was acidified with 2N HCl to afford solid which was filtered and air dried to afford 5-tert-butyl-2-methylfuran-3-carboxylic acid (0.29 g, 94% yield) as a white solid. MS (ESI) m/z: 183.1 (M+H+).
Reaction SMILES: C(OC(N1C[C@@H](C)N2[C@H](CC3C2=NC(CC)=C(CO)C=3)C1)=O)(C)(C)C.[C:26]([O:30][C:31]([N:33]1[CH2:45][C@@H:44]([CH3:46])[N:43]2[C@H:35]([CH2:36][C:37]3[C:42]2=[N:41][C:40]([CH:47]([F:49])[F:48])=[C:39]([CH:50]=[O:51])[CH:38]=3)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[BH4-].[Na+]>>[C:26]([O:30][C:31]([N:33]1[CH2:45][C@@H:44]([CH3:46])[N:43]2[C@H:35]([CH2:36][C:37]3[C:42]2=[N:41][C:40]([CH:47]([F:49])[F:48])=[C:39]([CH2:50][OH:51])[CH:38]=3)[CH2:34]1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(C(F)F)nc3N21
Agent: CCc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [BH4-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(C(F)F)nc3N21

Procedure:
This compound was prepared in analogy to example 15, intermediate b) from (4R,9aR)-6-difluoromethyl-7-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium borohydride.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[NH:13][C:12]3=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:13]([CH3:21])[C:12]3=[O:18])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)Nc1ccc(C23CC2C(=O)NC3=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C23CC2C(=O)N(C)C3=O)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1.2 g of 1-(4-acetylaminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione, 120 mg of sodium hydride and 25 ml of N,N'-dimethylformamide are stirred, under nitrogen, for 15 minutes at 50° C. The mixture is cooled to 20° C. and then a solution of 0.32 ml of methyl iodide in 2.5 ml of dimethylformamide is slowly added dropwise. The reaction mixture is stirred for 16 hours at room temperature. Excess sodium hydride is destroyed with methanol and the reaction mixture is freed from solvent in a high vacuum. The residue is partitioned repeatedly between ethyl acetate and a dilute solution of sodium chloride. The organic phases are dried over magnesium sulfate, filtered, concentrated, and the residue is crystallised from ethyl acetate/petroleum ether. The title compound is obtained in the form of white crystals with a melting point of 183°-184° C. and with Rf=0.37 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:19][CH:20]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.7 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (103 mg, 0.65 mmol, 1.00 eq) and 4-butylphenol (126 mg, 0.84 mmol, 1.29 eq) were dissolved in DMF (2.5 mL). Anhydrous K2CO3 (143 mg, 1.04 mmol, 1.59 eq) was added and the reaction mixture was stirred at room temperature for 6 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as colourless solid (190 mg, 0.70 mmol, quant. yield). Rf=0.33 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C15H17N2O3+ [M+H]+ 273.1234. found: 273.1226. 1H NMR (400 MHz, CDCl3) δ 9.05 (dd, J=2.9, 0.6 Hz, 1H, aromatic H), 8.46 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.32-7.21 (m, 2H, aromatic H), 7.11-7.02 (m, 2H, aromatic H), 7.00 (dd, J=9.0, 0.6 Hz, 1H, aromatic H), 2.69-2.60 (m, 2H, Ar—CH2CH2CH2CH3), 1.70-1.57 (m, 2H, Ar—CH2CH2CH2CH3), 1.39 (dq, J=14.6, 7.3 Hz, 2H, Ar—CH2CH2CH2CH3), 0.95 (t, J=7.3 Hz, 3H, Ar—CH2CH2CH2CH3). 13C NMR (101 MHz, CDCl3) δ 167.27, 150.75, 145.22, 140.86, 140.30, 134.92, 129.91, 121.22, 111.32, 35.21, 33.67, 22.51, 14.08.
Reaction SMILES: [CH:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(#N)C>[N:46]1([C:12]([C:9]2[CH:8]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[S:11][CH:10]=2)=[O:14])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: O=C(O)c1csc(C2CCCCC2)c1
Reactant: C1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1csc(C2CCCCC2)c1)N1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
5-(Cyclohexyl)-thiophene-3-carboxylic acid (0.03 g, 0.14 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.42 mmol), HATU (0.15 mmol) and azepane (0.14 mmol) were added and the reaction stirred at room temperature overnight. The resulting solution was purified directly by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.022 g). LCMS m/z 292.22 [M+H]+ RT=13.57 min (Analytical Method 1). 1H NMR δ (ppm) (CHCl3-d): 7.2 (s, 1H), 6.95 (s, 1H), 3.7-3.4 (m, 4H), 2.8 (m, 1H), 2.1 (m, 2H), 1.9-1.2 (m, 16H).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[Cl:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34]>C1C=CC=CC=1>[C:1]([NH:5][C:33]([NH:32][CH2:31][CH2:30][Cl:29])=[O:34])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(N)=O
Reactant: O=C=NCCCl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)NC(=O)NCCCl

Procedure:
A mixture of 71.1 g (1.0 mole) acrylamide, 0.5 g triethylamine, 0.5 g 2,6-ditert-butyl-4-methylphenol and 250 ml benzene is mixed with 110.8 g (1.05 mole) 2-chloroethyl isocyanate and heated in an autoclave over a period of 10 hours to 110° C. The finely crystalline precipitate obtained on cooling is filtered off. 140 g of substance is so obtained. It is recrystallized from 700 ml acetonitrile to yield 115 g (0.65 mole=65% of theory) white crystal needles having a melting point between 156° and 158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:14])[CH:9]([NH2:13])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[CH:16]([O:19][C:20]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:21]=1[C:22](=N)OCC)([CH3:18])[CH3:17].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:14][C:22]([C:21]3[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:20]=3[O:19][CH:16]([CH3:18])[CH3:17])=[N:13][CH:9]2[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCCC(N)C(N)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc(OC)cc1OC(C)C
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCCC1N=C(c2ccc(OC)cc2OC(C)C)NC1c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-pentane-1,2-diamine and ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 387.1840, calculated for C22H28N2O2Cl [(M+H)+]387.1834.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[C:5]2[CH2:21][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:41][CH2:42][CH3:43].CCOC(C)=O>CN(C=O)C>[CH2:41]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:19])[CH3:20])[CH:15]([CH3:16])[CH3:17])[CH:6]=[C:5]2[CH2:21][CH2:22][N:23]1[C:24](=[O:33])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]1=[O:32])[CH2:42][CH3:43]
Reactant: CCCI
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(c1)c(CCN1C(=O)c3ccccc3C1=O)cn2[Si](C(C)C)(C(C)C)C(C)C

Procedure:
Combine 2-(2-(5-hydroxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.7 g, 1.5 mmol), cesium carbonate (1 g, 3 mmol) and 1-iodopropane (0.4 g, 2.3 mmol) in DMF (25 mL) and stir at ambient temperature overnight Pour the reaction mixture into 50% EtOAc in hexanes and wash three times with brine. Dry the organic layer over MgSO4 and concentrate under vacuum to give an oil. Chromatograph the oil on silica gel eluting with 5% EtOAc in hexanes to give the title compound: ISMS 505 (M+1); 1H NMR (CDCl3) 7.80-7.78 (m, 2H), 7.67-7.65 (m, 2H), 7.30-7.27 (d, 1H), 7.12-7.11 (d, 1H), 7.02 (s, 1H), 6.77-6.74 (m, 1H), 4.01-3.96 (m, 4H), 3.12-3.08 (m; 2H), 1.86-1.81 (m, 2H), 1.64-1.57 (m, 3H), 1.08-1.04 (m, 21H).