Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([OH:38])[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[C:35]([CH3:37])[N:36]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])(=O)=O>O1CCCC1.C(OCC)(=O)C>[Si:53]([O:38][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:8][N:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]2[N:34]=[C:35]([CH3:37])[N:36]=[C:10]12)([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C2CCCCC2)c2nc(C)nn12
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O[Si](C)(C)C(C)(C)C)C2CCCCC2)c2nc(C)nn12
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution (15 mL) of 4′-{[4-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.64 g) in tetrahydrofuran were added 2,6-lutidine (0.22 mL) and tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.43 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hr, diluted with ethyl acetate, washed with water and then with 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 to give the title compound as a colorless solid (0.52 g, 75%).
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9](=[O:11])[CH3:10])C=CC=CC=1.[CH:24]([C:26]1[O:30][N:29]=[C:28]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:27]=1)=O>ClCCl>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[C:28]1[CH:27]=[C:26]([CH:24]=[CH:8][C:9](=[O:11])[CH3:10])[O:30][N:29]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(C2CCCCO2)no1
Solvent: ClCCl
Product: CC(=O)C=Cc1cc(C2CCCCO2)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
47 g of 1-triphenylphosphoranylidene-2-propanone were dissolved in 50 ml of dichloromethane, and 27 g of 5-formyl-3-tetrahydropyran-2-ylisoxazole were added. The reaction mixture was stirred for 1 day at room temperature and then evaporated down, the residue being stirred in methyl tert-butyl ether. After the triphenylphosphine oxide has been separated off, 43 g of a yellow oil remained.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg) in acetonitrile (3 ml) was added a solution of 2% HF in aqueous acetonitrile (80 μl), and the mixture was stirred at room temperature. After 2 hours, the solution was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (63 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[CH2:1])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CCCC1CCC(CCc2ccc(C3CCC(C=O)CC3)cc2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(c2ccc(CCC3CCC(CCC)CC3)cc2)CC1
Yield: 80.1 %

Procedure:
Potassium tert-butoxide (0.86 g, 7.01 mmol) was added slowly with stirring for 3 minutes to 32 ml of solution including methyltriphenylphosphonium bromide (3 g, 8.41 mmol) dissolved in THF. Then, the solution was stirred for 30 minutes at a room temperature and THF solution (25 ml) of 4-{4-[2-(4-propyl-cyclohexyl)ethyl]phenyl}cyclohexane carbaldehyde (2.39 g, 7.01 mmol) was added slowly dropwise to reaction mixture, and then was stirred at a room temperature for 24 hours. The precipitate was filtered under reduced pressure and the filtrate was washed by water (100 ml) and extracted with ether (20 ml×1 time). The aqueous layer was extracted by chloroform (20 ml×3 times). The organic layer was collected, washed by NaCl solution, dried by anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane, Rf=0.36) and was recrystallized by addition of chloroform and ethanol to obtain 1.9 g (80%) of 1-[2-(4-propyl-cyclohexyl)ethyl]-4-(4-vinyl-cyclohexyl)benzene.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([CH3:24])=[CH:17][N:16]=1.Cl>COCCOC>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([CH3:24])=[CH:17][N:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)c1ncc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diethyl malonate (72 g, 0.436 mol) in DME (200 mL) is added dropwise to a magnetically stirred suspension of NaH (23 g, 0.58 mol) in dry 1,2-dimethoxyethane (DME, 350 mL). The mixture is stirred at room temperature for 1 hour and then a solution of 2-chloro-5-methyl-3-nitro-pyridine (50 g, 0.290 mol) in DME (100 mL) is added to give a dark red solution. After stirring for 18 hours, the reaction mixture is poured into ice-cold water and acidified to pH 3 with 6N HCl solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water, brine, dried over Na2SO4, and concentrated. The excess diethymalonate is removed at 50° C. under high vacuum to give 2-(5-Methyl-3-nitro-pyridin-2-yl)-malonic acid diethyl ester i as a dark red-colored thick residue; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=9 Hz, 6H), 4.26 (q, J=9 Hz, 4H), 8.27 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:4]=2[CH2:3][CH2:2]1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>CC(C)=O>[C:21]1([C:19]2[C:10]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[C:5]3[N:6]([CH:18]=2)[CH:7]=[CH:8][C:9]2[O:1][CH2:2][CH2:3][C:4]3=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)NCCCc1nccc2c1CCO2
Solvent: CC(C)=O
Product: CC(=O)NCCc1c(-c2ccccc2)cn2ccc3c(c12)CCO3
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A mixture of N-[3-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)propyl]acetamide (24.5 mg, 0.111 mmol) and 2-bromo-1-phenylethanone (44.2 mg, 0.222 mmol) in acetone (3 mL) was heated under reflux for 13 hr. The reaction mixture was allowed to cool to room temperature and the resulting crystals were collected by filtration and washed with acetone. The crystals were dissolved in ethanol (3 mL), sodium hydrogen carbonate (50 mg) was added, and the mixture was heated under reflux for 1 hr. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/50) to give the title compound (12.7 mg, yield 36%).
Reaction SMILES: [BrH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1.[O:26]1[CH2:28][CH2:27]1>CO>[BrH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:28][CH2:27][OH:26])[CH2:24][CH2:25]2)=[CH:5][CH:4]=1
Reactant: C1CO1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Solvent: CO
Product: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred mixture of 40.4 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine hydrobromide and 400 parts of methanol are added 8.8 parts of oxirane and stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The precipitated product is filtered off and dried, yielding 29 parts (64%) of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol monohydrobromide; mp. 248.2° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][C:29]1[NH:30][C:31]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:32][N:33]=1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:31]2[N:32]([N:33]=[C:29]([CH3:28])[N:30]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: Cc1nnc(NC2CCOCC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1 g) and 5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH3:21])[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:38]([NH2:42])[CH2:39][CH2:40][CH3:41]>O1CCCC1.C(Cl)Cl>[CH2:38]([NH:42][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH3:21])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CC)NC(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
2.42 g of 1-(N-(tert-butoxycarbonyl)-2(S)-aminobutyryl)-L-proline (8.05 mmol) prepared as in Example 2 c) are dissolved in dry tetrahydrofuran (15 ml). The solution is cooled in an ice/salt bath and 0.927 g of N-ethylmorpholine (8.05 mmol) and 1.10 g of isobutyl chloroformate (8.05 mmol) are then added. The solution is stirred for 45 minutes and 0.59 g (8.05 mmol) of n-butylamine is added. After stirring overnight, methylene chloride (200 ml) is added and the mixture is washed with 10% citric acid (2×100 ml) and then with 5% NaHCO3 (2×100 ml). The organic phase is dried (Na2SO4) and evaporated under vacuum. A syrup is obtained. The deprotection is carried out without characterization.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[C:7](=[S:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1.[OH-].[Na+]>>[CH2:1]([S:13][C:7]1[C:6]([F:5])=[CH:11][NH:10][C:9](=[O:12])[N:8]=1)[CH:2]=[CH2:3]
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Product: C=CCSc1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
Allyl bromide (0.013 mol) was added to a solution of 5-fluoro-4-thiouracil (0.01 mols), 8.73 mols NaOH (25 mls) and the reaction mixture stirred at room temperature for 5 hrs. The reaction mixture was then extracted with chloroform (2×5 ml), before the aqueous solution was acidified with HCl when the titled compound was precipitated; yield 40%, m.p. 150°-152° C. (water). (Found: C, 44.87; H, 3.84. Calc. for C7H7SFN2O; C, 45.15; H, 3.80).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]2[CH:15]=[C:16]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]2[CH:21]=[C:20]4[C:33]([CH3:41])([CH3:40])[C:34]5[C:39]([C:19]4=[CH:18][C:17]3=2)=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:2]=1.Br[C:43]1[CH:44]=[C:45]([C:49]2[N:54]=[C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:52]=[C:51]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[N:50]=2)[CH:46]=[CH:47][CH:48]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:61]1([C:51]2[CH:52]=[C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[N:54]=[C:49]([C:45]3[CH:46]=[C:47]([N:12]4[C:13]5[CH:1]=[CH:2][C:3]([C:14]6[CH:15]=[C:16]7[C:24](=[CH:25][CH:26]=6)[N:23]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[C:22]6[CH:21]=[C:20]8[C:33]([CH3:41])([CH3:40])[C:34]9[C:39]([C:19]8=[CH:18][C:17]7=6)=[CH:38][CH:37]=[CH:36][CH:35]=9)=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:48]=[CH:43][CH:44]=3)[N:50]=2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CC1(C)c2ccccc2-c2cc3c4cc(-c5ccc6[nH]c7ccccc7c6c5)ccc4n(-c4ccccc4)c3cc21
Reactant: Brc1cccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5ccc6c(c5)c5ccccc5n6-c5cccc(-c6nc(-c7ccccc7)cc(-c7ccccc7)n6)c5)ccc4n(-c4ccccc4)c3cc21

Procedure:
19.50 g (37.17 mmol) of 7-(9H-carbazol-3-yl)-12,12-dimethyl-10-phenyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene 23, 15.83 g (40.88 mmol) of 2-(3-bromophenyl)-4,6-diphenylpyrimidine 14 and 10.91 g (113.50 mmol) of NaOtBu are suspended in 600 ml of p-xylene. 168.73 mg (0.75 mmol) of Pd(OAc)2 and 2.3 ml of a 1M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 19 h. After cooling, the organic phase is separated off, washed three times with 100 ml of water and subsequently evaporated to dryness. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. The yield is 15.44 g (50%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.CO>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(F)cc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 4-fluorobenzoyl chloride (0.45 g, 2.8 mmol). The mixture was stirred at room temperature overnight followed by addition of MeOH (1 mL). After filtration, the resulting solid was washed with CH2Cl2 then recrystallized in CH3OH to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-fluoro-benzamide as a white solid (0.5 g, 59%): mp, 233-235° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.6 (96%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.86-2.98 (m, 1H), 4.95 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.30-7.38 (m, 2H), 7.72-7.86 (m, 3H), 7.96-8.03 (m2H), 9.18 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.35, 48.86, 115.15, 115.44, 121.87, 127.12, 129.91, 130.03, 130.37, 131.52, 133.05, 134.80, 139.21, 162.35, 165.54, 165.64, 166.95, 167.52, 169.82, 172.74. Anal Calcd for C21H16FN3O5: C, 66.61; H, 3.94; N, 10.26; F, 4.64. Found: C, 61.53; H, 3.82; N, 10.20; F, 4.72.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[C:17]([O:19]CC)=O)=[CH:4][C:3]=1[F:22].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[C:17]([NH:29][C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)=[O:19])=[CH:4][C:3]=1[F:22]
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1nc2cccnc2n1-c1ccc(Cl)c(F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1ccc(NC(=O)c2nc3cccnc3n2-c2ccc(Cl)c(F)c2)n1

Procedure:
To a solution of ethyl 3-(4-chloro-3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxylate (C13) (32 mg, 0.10 mmol) and 1-methyl-1H-pyrazol-3-amine (29 mg, 0.30 mol) in toluene (3 mL) was added trimethylaluminum (2 M solution in toluene, 0.3 mL, 0.6 mmol) at room temperature. The reaction mixture was irradiated in a microwave reactor at 150° C. for 1 hour, whereupon it was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via reversed phase HPLC (Column: Agella Venusil ASB-C18, 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: 0.225% formic acid in acetonitrile; Gradient: 33% to 63% B) afforded the product as a yellow solid. Yield: 2.0 mg, 5.4 μmol, 5%. LCMS m/z 371.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.47 (br d, J=4.6 Hz, 1H), 8.32 (br d, J=8 Hz, 1H), 7.69 (dd, J=8, 8 Hz, 1H), 7.48-7.56 (m, 3H), 7.35 (br d, J=8 Hz, 1H), 6.52-6.55 (m, 1H), 3.83 (s, 3H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.[CH3:36][O:37][C:38]([C:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1)=[O:39]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:36][O:37][C:38]([C:40]1([C:43](=[O:44])[NH:29][C:26]2[CH:25]=[CH:24][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][CH:27]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(C(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
HOBt (70 mg, 0.54 mmol), DMAP (110 mg, 0.9 mmol), EDCI.HCl (104 mg, 0.54 mmol) followed by biphenyl-4-ylamine (92 mg, 0.54 mmol) were added to a stirred solution of cyclopropane-1,1-dicarboxylic acid methyl ester (65 mg, 0.45 mmol) in DMF (2 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with water. The resulting precipitate was isolated by filtration and dried to afford 100 mg (75%) of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH:37]([CH2:39][CH3:40])[CH3:38]>>[CH3:38][CH:37]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:39][CH3:40]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: CCC(C)Br
Product: CCC(C)Oc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 2-bromo-butane
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:9].C[N+]1(C)CCCCC1.C(Cl)(Cl)=O.[ClH:22]>>[Cl:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([Cl:22])=[O:7].[C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Cl-]
Reactant: Cl
Agent: C[N+]1(C)CCCCC1
Agent: O=C(Cl)Cl
Agent: O=C1CCCCCO1
Product: O=C(Cl)CCCCCCl

Procedure:
456 parts of 6-caprolactone and 9 parts of N,N-dimethylpiperidinium chloride are initially taken in the stirred reactor described in Example 1. 380 parts of phosgene and 70 parts of hydrogen chloride are passed in at 170°-175° C. in the course of 7 hours. The reaction mixture is then kept at this temperature for a further hour. Any phosgene and hydrogen chloride still present are blown out with nitrogen, and the reaction mixture is then worked up by distillation under reduced pressure. 424 parts of 6-chlorohexanoyl chloride and 86 parts of caprolactone are obtained. The conversion is 81% and the yield is 77.3%, based on lactone used.
Reaction SMILES: [CH3:1][C:2]([C:5]1[NH:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:7]=2[N:6]=1)([CH3:4])[CH3:3].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[C:7]3[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=[C:5]2[C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:19][CH:18]=1
Reactant: CC(C)(C)c1nc2c([nH]1)CCCCC2=O
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
Tetrabutylammonium bromide (1.33 g) was added to a stirred mixture of Intermediate 13 (1.7 g), 4-chlorobenzyl bromide (1.86 g) in sodium hydroxide 20% aq. (12 mL) and toluene (6 mL). The RM was stirred at room temp under nitrogen atm for 3 hours. An excess of sat. NH4Cl aq. solution was added and the mixture was extracted with EtOAc (3×30 ml). The organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give crude material. It was purified by reverse phase chromatography using an acetonitrile-0.1% NH3:water—with an amonium carbonate buffer modifier (pH=10) 5%-95% gradient. The desired fractions were combined and concentrated under vacuum to yield the title compound (650 mg). LC/MS MH+ 331 Rt 2.04 min (5 minute run).