Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrCC1C=CC(C2C=CC=CC=2C(C2C=CC=CC=2)=O)=CC=1>C(#N)C>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C(c1ccccc1)c1ccccc1-c1ccc(CBr)cc1
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 80 °C

Procedure:
To a 200-mL flask equipped with a reflux condenser were added 25.1 g of 4-methylbenzophenone (Aldrich), 22.8 g of N-bromosuccinimide (Wako Pure Chemical Industries, Ltd.), 0.54 g of benzoyl peroxide (containing 20% water, Wako Pure Chemical Industries, Ltd.), and 80 g of acetonitrile, which were heated to 80° C. and were made react under reflux for 2 hours. After cooling, the solvent was distilled away and the residue was recrystallized from 160 g of methanol, so that 26 g of intermediate (H10) (white crystals) was obtained. As a result of an analysis by 1H-NMR {300 MHz, CDCl3, δ (ppm): 7.9-7.7 (m, 4H), 7.6 (t, 1H), 7.55-7.4 (m, 4H), 4.5 (s, 2H)}, it was confirmed that this intermediate (H10) was 4-bromomethylphenylbenzophenone.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:53])[C@H:47]([CH2:49][C:50](=[O:52])[NH2:51])[NH2:48])(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([NH:48][C@H:47]([C:46]([OH:45])=[O:53])[CH2:49][C:50](=[O:52])[NH2:51])=[O:34])=[CH:36][CH:37]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)O)cc2)cc1

Procedure:
The product from Example 95C and L-aspargine tert-butyl ester hydrochloride were processed as described in Example 251A and 258B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.18-13.09 (br.s, 1 H), 8.94 (s, 1 H), 8.28 (d, 1 H), 7.39 (s, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.91 (s, 1 H), 6.84 (d, 2 H), 4.60 (dd, 1 H), 4.49 (s, 2 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 2.91 (s, 3 H), 2.60 (d2 H), 2.39 (s, 3 H); MS ((ESI+) m/z 661 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)O)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)N2CCCCC2)=C(C)C1=O
Yield: 34.5 %

Procedure:
3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (20 mg, 0.058 mmol) obtained in Example 69 and piperidine (0.009 ml, 0.087 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (8.4 mg, 0.020 mmol, yield 34%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH2:12][OH:13].[C:17]([O:21]C)(=[O:20])[CH:18]=[CH2:19].CC(C)([O-])C.[K+].O1CCCC1.C(O)(C)(C)C.Cl>>[CH2:12]([O:13][CH2:19][CH2:18][C:17]([OH:21])=[O:20])[CH:11]=[C:10]([CH2:9][CH2:8][CH:7]=[C:6]([CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])[CH3:15])[CH3:14]
Reactant: C=CC(=O)OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCOCCC(=O)O

Procedure:
All-trans-farnesol was reacted with methyl acrylate in the presence of one equivalent of 0.1 equivalent of potassium-tert butoxide/tetrahydorfuran/t-butanol for three hours at room temperature. The solution was acidified with 0.1N HCl, evaporated to dryness, and purified by thin layer chromatography on silica. The free acid was prepared by treatment of the ester with potassium hydroxide in methanol. The product showed the anticipated nmr and infrared spectra.
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:6]2[CH2:7][CH2:8][C:3]([CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[N:28][CH:29]=1
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a solution of ii (0.9 g, 4.35 mmol) in EtOH (10 mL) was added DIPEA (2.30 mL, 13 mmol) at RT and the mixture stirred at RT for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.7 g, 3.6 mmol). The mixture was heated at 70° C. for 1 h. The solvent was evaporated and the crude residue purified by chromatography on silica eluting with 1.5% EtOAc:hexane to obtain iii (0.90 g, 75%). 1H NMR (DMSO-d6, 400 MHz): δ 1.17 (s, 3H), 1.21 (t, J=7.20 Hz, 3H) 1.40 (m, 2H), 2.00 (m, 2H), 3.24 (m, 2H), 4.11 (m, 2H), 4.15 (q, J=7.20 Hz, 2H), 8.43 (s, 2H). MS: 328.08 [M+H]+.
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:8][C:7](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:16](OCC1C=CC=CC=1)=O.C[O:28][C:29](=O)[C@@H:30]1CC(=C)CN1C(OCC1C=CC=CC=1)=O>>[CH2:9]([C@@H:7]1[CH2:6][N:5]2[C@H:4]([CH2:3][C:29](=[O:28])[CH2:30][CH2:16]2)[CH2:8]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)[C@@H]1CC(=Cc2ccccc2)CN1C(=O)OCc1ccccc1
Product: O=C1CCN2C[C@@H](Cc3ccccc3)C[C@H]2C1
Yield: 4 %

Procedure:
In a similar manner to the procedures described in Preparative Examples 8(ii)′, 8(iii)′, 8(iv)′, 8(v)′ and 8(vi)′ above, reactions were conducted in turn, using (S)-1-benzyloxycarbonyl-4-benzylideneproline methyl ester [prepared as described in Preparative Example 26′ above] instead of (S)-1-benzyloxycarbonyl-4-methylideneproline methyl ester, to give the title compound as a brown oil (yield: 4%).
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([C:8]([OH:10])=[O:9])[NH2:7])[CH2:4][CH2:3][CH2:2]1.Cl[C:12]([O:14][CH3:15])=[O:13]>[OH-].[Na+].O>[CH3:15][O:14][C:12]([NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: NC(CC1CCC1)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NC(CC1CCC1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4.3 g (30 mmol) of 3-cyclobutyl-DL-alanine [A. Burger et al., J. Med. Chem. 6, 221 (1963)] is dissolved in 15 ml of 2M NaOH solution, cooled to 0° C. and simultaneously 16.5 ml of 2M NaOH solution and 2.55 ml (33 mmol) of methyl chloroformate are added with vigorous stirring. Stirring is continued at this temperature for 30 minutes and at room temperature for 2 hours. The reaction mixture is diluted with 40 ml of water, extracted with 10 ml of diethyl ether, then acidified to pH3 with 3M HCl. The product is extracted with ethyl acetate (4×20 ml), the extracts are pooled, washed with 20 ml of water, dried over anhydrous sodium sulphate and evaporated at a pressure of 2.0-2.5 kPa. The oily residue [5.3 g (88%), Rf(7)=0.61] is used without further purification in the next step.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)(=O)=O.C(N(CC)CC)C.[I-].[Na+]>>[C:13]1([N:11]2[CH:12]=[C:8]([CH:7]=[CH2:6])[N:9]=[N:10]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)OCCc1cn(-c2ccccc2)nn1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=Cc1cn(-c2ccccc2)nn1

Procedure:
2-(1-phenyl-1H-1,2,3-triazol-4-yl)ethyl methanesulfonate (1.43 g, 5.35 mmol), triethylamine (1.62 g, 16.05 mmol) and sodium iodide (2.41 g, 16.05 mmol) were added to a vial to produce 1-phenyl-4-vinyl-1H-1,2,3-triazole.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[K+].[I:14]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.O>[I:14][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=2)[NH:1][CH:2]=1
Reactant: N#Cc1cnc2[nH]ccc2c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnc2[nH]cc(I)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
To a solution of 35 (3.0 g, 21.0 mmol) in DMF (53 mL) was added KOH (4.35 g, 77.5 mmol, pellets) and the reaction mixture stirred for 20 min., cooled to 0° C., and treated with iodine (5.32 g, 21.0 mmol). It was stirred at room temperature for 50 min then poured onto a mixture of water (306 mL)/sat. aqueous Na2S2O3 (46 mL). The resulting solid was filtered off and washed with water (2×) to give 36 (3.57 g, 63%) as creamy solid; 1H NMR (400 MHz, DMSO) δ 7.96 (s), 8.25 (s), 8.64 (s), 12.74 (NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:36](CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24](=[O:26])[NH2:36])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
Acid compound 6 (1.5 g, 3.3 mmol) was dissolved in DCM (25 mL). Triethylamine (0.55 mL, 3.94 mmol) and BOP reagent (1.6 g, 3.61 mmol) were added and the reaction mixture stirred at room temperature for 15 min under an atmosphere of argon. Ammonia gas was then bubbled gently through the solution for 15-20 min to complete the reaction. Excess ammonia was degassed, the solvent was removed under reduced pressure and the residue was suspended in EtOAc (75 mL). The organic layer was washed with 0.5 N NaOH (2×10 mL), water (2×25 mL), and brine (1×30 mL), dried and concentrated under reduced pressure to yield the amide compound 11 (1.5 g, ˜99%). 1H NMR (DMSO-d6): 7.27 (br, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.75 (br, 1H), 4.53 (m, 1H), 2.91 (s, 3H), 2.75-2.83 (m, 7H), 2.33 (t, J=7.6 Hz, 2H), 1.32 (s, 9H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([CH2:21][O:22][C:23]2[CH:33]=[CH:32][C:26]([O:27][CH:28]3[CH2:31][NH:30][CH2:29]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19]1>>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([N:30]2[CH2:31][CH:28]([O:27][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:18]4[CH2:19][CH2:20]4)=[CH:33][CH:32]=3)[CH2:29]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cc(OC2CNC2)ccc1OCC1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1

Procedure:
Example 8.3 is prepared analogously to 8.1. (S)-[1-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.3) and 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1) are used as starting materials and the reaction temperature is 45° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].O.[CH3:13]O>S(=O)(=O)(O)O>[CH3:13][C:4]1[C:3]([F:11])=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)ccc(Br)c1F
Temperature: 25 °C

Procedure:
4-Bromo-3-fluorobenzoic acid (WAKO, 1.0 g) was dissolved in methanol (10 mL), followed by addition of concentrated sulfuric acid (10 drops). The mixture was refluxed for three hours. After cooling to room temperature, water was added and the extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the target compound (618 mg).
Reaction SMILES: [Ca].[C:2]([C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:9]P(=O)([O-])OCC)([CH3:5])([CH3:4])[CH3:3]>>[C:20]([C:17]1[CH:16]=[C:8]([CH:7]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:18]=1[OH:19])[CH2:9][C:7]1[C:8]([CH3:9])=[C:16]([CH2:9][C:8]2[CH:7]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:18]([OH:19])=[C:17]([C:20]([CH3:22])([CH3:23])[CH3:21])[CH:16]=2)[C:17]([CH3:20])=[C:18]([CH2:9][C:8]2[CH:16]=[C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:18]([OH:19])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=2)[C:6]=1[CH3:2])([CH3:22])([CH3:23])[CH3:21]
Reactant: CCOP(=O)([O-])Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Ca]
Product: Cc1c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
calcium salt of monoethyl 3,5-di-t-butyl-4-hydroxy-benzylphosphonate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.C(N(CC)CC)C.[NH2:15][CH2:16][CH:17]([OH:33])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:21]=1>C1COCC1>[NH2:7][C:5]1[S:6][C:2]([NH:15][CH2:16][CH:17]([OH:33])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:21]=2)=[N:3][N:4]=1
Reactant: NCC(O)COc1cccc(CN2CCCCC2)c1
Reactant: Nc1nnc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nnc(NCC(O)COc2cccc(CN3CCCCC3)c2)s1

Procedure:
0.54 g (3 mmol) of 5-bromo-1,3,4-thiadiazole-2-amine and 0.45 ml of triethylamine are added to 0.8 g (3 mmol) of 1-amino-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol in 20 ml of THF and the mixture is reacted in a manner analogous to Example 51. The oil obtained is purified by column chromatography (silica gel; ammoniacal. Methanolchloroform solution (5+95)).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:19]([N:38]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[CH:56]=[CH:55][C:52]([CH2:53]Br)=[CH:51][CH:50]=2)=[N:41][N:40]=[N:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([C:5]1[N:6]([CH2:53][C:52]2[CH:51]=[CH:50][C:49]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[C:42]3[N:38]([C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:39]=[N:40][N:41]=3)=[CH:56][CH:55]=2)[C:7]([C:15]#[N:16])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)(O)CC)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(C(C)(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 72 %

Procedure:
Following a procedure similar to that described in Example 18(a), but using 465 mg of 2-butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)imidazole (prepared as described in Preparation 19), 92 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 1.11 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 1.00 g of the title compound was obtained as a gum.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][N:12]3[C:13]4[C:9](=[CH:8][C:7]([CH2:6][CH:5]([O:16][CH2:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:23]=2)[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(OC)cc(OC)c3)oc2C)c1)C(=O)O
Yield: 50 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole, the title compound was obtained in 50% yield as a colourless solid. MS: (M−H)− 463.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][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:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])#[N:23].C(N(CC)CC)C>C1COCC1>[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][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])=[O:28])#[N:23]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and m-cyanobenzoyl chloride (0.4 g, 2.5 mmol) in THF (30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (40 mL). The mixture was filtered, and the solid was slurried with warmed ethanol (20 mL) to give 3-cyano-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.8 g, 92%) as a white solid: mp 282-284° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.34-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.41-4.62 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.8 and 13 Hz, 1H, CH), 7.48-7.74 (m, 4H, Ar), 8.01 (d, J=7.7 Ha, 1H, Ar), 8.17 (d, J=7.9 Hz, 1H, Ar), 8.31 (s, 1H, Ar), 9.28 (t, J=5.0 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.69, 31.17, 46.26, 51.60, 111.50, 118.26, 121.79, 128.35, 129.80, 130.82, 130.89, 131.65, 132.08, 134.14, 134.79, 135.00, 140.25, 164.54, 168.02, 170.98, 172.81; Anal. calcd. for C22H18N4O4: C, 65.67; H, 4.51; N, 13.92. Found: C, 65.38; H, 4.42; N, 13.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>O>[C:25]([NH:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH3:18])(=[O:27])[CH3:26]
Reactant: CC(CCN)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC(C)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 2.6 g of of 3-(4'-chloro-4-biphenylyl)butylamine, 12 ml of pyridine and 1 ml of acetyl chloride is allowed to stand for 2 hours, decomposed with water and worked up in the customary manner to give 1-acetamido-3-(4'-chloro-4-biphenylyl)-butane, m.p. 118°-120°.
Reaction SMILES: [Si](O[CH2:9][C@H:10]([NH:17][C:18](=[S:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[I:25][C:21]1[CH:20]=[C:19]([C:18]2[S:26][CH2:9][C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](NC(=S)c1cccc(I)c1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Ic1cccc(C2=N[C@H](c3ccccc3)CS2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
To a solution of N-(1-tert-butyldimethylsilyloxy-2(R)-phenylethan-2-yl)-3-iodobenzthiamide (8.1 g, 16 mmol) in THF (70 ml) was added dropwise tetrabutyl-ammonium fluoride (1M in THF, 21 ml). The reaction mixture was stirred at room temperature for 4 hours, solvent removed by evaporation and the resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/n-hexane (=1:7) to afford 4,5-dihydro-2-(3-iodophenyl)-4(R)-phenylthiazole (2.46 g, 41%).
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH2:14].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1
Reactant: Nc1cc2c3c(c1)CCCC3CCC2
Reactant: CCOC(=O)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4CCC3)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
5,6,6a,7,8,9-Hexahydro-4H-2-phenalenylamine (0.100 g) was added with ethyl 2-chloropyrimidine-5-carboxylate (0.101 g) and potassium carbonate (0.400 g), and the mixture was stirred overnight at 110° C. The reaction mixture was left to cool and then added with water, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:20) to obtain the title compound (0.167 g, yield: 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]([CH3:14])[CH3:13])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]([CH3:14])[CH3:13])=[N:9][N:8]=2)[CH:7]=1
Reactant: CN(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1nnc2ccc(F)cn12
Temperature: 60 °C
Reaction time: 9 h
Yield: 14.5 %

Procedure:
To a solution of Intermediate 59a (590 mg, 2.98 mmol), Ph3P (1.56 g, 5.96 mmol) and Et3N (1.20 g, 11.9 mmol) in THF (40 mL) was added hexachloroethane (1.41 g, 5.96 mmol) and the mixture stirred at 60° C. for 9 h. The mixture was diluted with EtOAc (100 mL), washed with water, brine, dried (MgSO4) and then concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, then triturated with diethyl ether to give the title compound (78 mg, 14%). LCMS (Method 1): Rt 2.24 min, m/z 181 [MH+].
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C1(=O)CCCC1.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N:1]1([C:17]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CN(C)C1(C#N)CCCC1
Reactant: C1=CCNC1
Agent: [C-]#N
Agent: [K+]
Solvent: O=C1CCCC1
Solvent: O
Product: N#CC1(N2CC=CC2)CCCC1
Yield: 64 %

Procedure:
The title compound (2.8 g; 64%) was prepared from 3-pyrroline (1.86 g; 27 mmol), cyclopentanone (2.26 g; 27 mmol) and potassium cyanide (1.75 g; 27 mmol) in water (15 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.85 (6H, m), 2.08 (2H, m), 3.61 (4H, s), 5.78 (2H, s).