Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C2C(I)=CN([C@H]3CC[C@H](N4CCN(C)CC4)CC3)C=2N=CN=1.C1(OC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2C)C=CC=CC=1.[Cl:48][C:49]1[C:50]2[C:57]([C:58]3[CH:59]=[CH:60][C:61]([O:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[C:62]([CH:65]=3)[C:63]#N)=[CH:56][N:55]([C@H:73]3[CH2:78][CH2:77][C@H:76]([N:79]4[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]4)[CH2:75][CH2:74]3)[C:51]=2[N:52]=[CH:53][N:54]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[C:67]1([O:66][C:61]2[CH:60]=[CH:59][C:58]([C:57]3[C:50]4[C:49]([Cl:48])=[N:54][CH:53]=[N:52][C:51]=4[N:55]([C@H:73]4[CH2:74][CH2:75][C@H:76]([N:79]5[CH2:80][CH2:81][N:82]([CH3:85])[CH2:83][CH2:84]5)[CH2:77][CH2:78]4)[CH:56]=3)=[CH:65][C:62]=2[CH3:63])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(C#N)c4)c4c(Cl)ncnc43)CC2)CC1
Agent: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1ccccc1
Solvent: CC#N
Product: Cc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(Cl)c23)ccc1Oc1ccccc1

Procedure:
The title compound was prepared in an 82% yield from from trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine and 2-methyl-4-(4,4,5,5-tetrametyl-1,3,2-dioxaborolan-2-yl)phenyl phenyl ether in similar manner to that described for the preparation of trans-5-(4-chloro-7-(4-(4-methylpiperazino)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (s, 1H), 7.98(s, 1H), 7.49 (s, 1H), 7.37(m, 3H), 7.10(t, 1H), 6.95(m, 3H), 4.72(m, 1H), 2.2-2.6(m, 9H), 2.23(s, 3H), 2.17(s, 3H), 2.01(m, 6H), 1.48 (m, 2H); MS MH+516.4; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 10.53 min.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C:5]([CH:18]([CH3:20])[CH3:19])=[CH:4][C:3]=1[O:21][CH3:22].[F-].[K+].[F:25][C:26](I)([F:28])[F:27].O>CN(C=O)C.[Cu]I>[CH:18]([C:5]1[CH:4]=[C:3]([O:21][CH3:22])[C:2]([C:26]([F:28])([F:27])[F:25])=[CH:7][C:6]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:20])[CH3:19]
Reactant: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1I
Reactant: FC(F)(F)I
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(F)(F)F
Yield: 107.9 %

Procedure:
To a hot mixture of 1-Iodo4-isopropyl-2-methoxy-5-(toluene4-sulfonyl)-benzene (0.5 g, 1.12 mmol), CuI, KF in anhydrous DMF (10 ml) at 120° C. oil bath temperature, was added trifluoromethyl iodide (0.64 g, 4.48 mmol) in portions over 30 min. The reaction mixture was heated for 4 hrs and poured into H2O (100 ml). The insoluble solid, which was collected by filtration was triturated with methylene chloride, filtered and concentrated to give 1-Isopropyl-5-methoxy-2-(toluene4-sulfonyl)4-trifluoromethyl-benzene (0.45 g, 100%) as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(CC)CC>C1COCC1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][NH:7][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:15]
Reactant: CCOC(=O)CCCN
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 94.5 %

Procedure:
Methanesulfonyl chloride (4.10 g, 35.8 mmol) was added to a suspension of ethyl 4-aminobutyrate hydrochloride (6.00 g, 35.8 mmol) and Et3N (10.8 mL, 77.4 mmol) in THF (230 mL). The resulting suspension was stirred at room temperature for 43 h. The reaction mixture was filtered and the filtrate was concentrated. Flash chromatography (1:1 EtOAc:hexanes to EtOAc) afforded the title compound (7.08 g). 1H NMR (400 MHz, CDCl3) δ4.51 (s, 1H), 4.12 (q, 2H), 3.18 (q, 2H), 2.94 (s, 3H), 2.40 (t, 2H), 1.85-1.92 (m, 2H), 1.24 (t, 3H); MS 210 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][N:14]([CH3:27])[CH2:15][CH2:16][O:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>>[CH3:13][N:14]([CH3:27])[CH2:15][CH2:16][O:17][N:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CN(C)CCONCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CN(C)CCON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 30 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-(2-dimethylamino-ethyl)-N-(4-fluorobenzyl)-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (30% yield): mp 95-96° C. (ether-hexane). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 1.70 (6H, s, CH3), 2.16 (6H, s, NCH3), 2.44 (2H, t, J=5.3 Hz, CH2), 3.97 (2H, t, J=5.3 Hz, CH2), 4.79 (2H, s, NCH2), 6.52 (1H, s, CH), 7.18 (2H, m, aromatics), 7.34 (2H, m, aromatics). Anal. calcd for C18H23FN2O5: C, 59.00; H, 6.32; N, 7.64. Found: C, 58.73; H, 6.13; N, 7.40.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:14])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:12]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:14])[CH3:11]
Reactant: CC(C)=O
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(CNC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A mixture of 4-methoxybenzylamine (1.37 g, 10 mmol) and acetone (0.81 mL, 11 mmol) in dry dichloroethane (20 mL) were stirred at room temperature for 30 minutes. To the solution was added sodium triacetoxyborohydride (3.18 g, 15 mmol) and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was quenched with 1 N NaOH (50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×20 mL). The combined extracts were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The residue was chromatographed eluting with 10% MeOH in dichloromethane with 1% triethylamine to provide 1.53 g of oil (85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]4[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH2:17]([N:14]1[C:13]2[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=2[O:11][C:10]2=[C:5]3[C:6](=[N:8][C:9]2=[C:15]1[N:8]([CH2:9][CH3:10])[CH2:6][CH3:5])[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4]3)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c2Oc2ccccc2N1Cc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCN(CC)C1=C2N=c3cc(Cl)ccc3=C2Oc2ccccc2N1Cc1ccccc1

Procedure:
A mixture of 7.48g of 3-chloro-7-benzyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one and 5.25g of phosphorous pentachloride in 200ml of benzene was stirred at reflux for 41/2 hours. A yellow solid precipitated. To this suspension was added at reflux with stirring, 14.6g of diethylamine. The reaction was stirred at reflux for another 2 hours, cooled, diluted with an equal volume of ether, washed twice with H2O, dried and concentrated to an orange oil. The oil crystallized on rubbing with ethanol. Recrystallization for ethanol gave analytical material, mp. 132°-4°.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH:43]1([CH:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>ClCCl>[C:43]1([CH:49]([CH:51]2[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]2)[O:2][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: OC(c1ccccc1)C1CCCCC1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)OC(c1ccccc1)C1CCCCC1
Yield: 25.9 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (71 mg, 0.19 mmol), 4-N,N-dimethylaminopyridine (7.5 mg, 0.06 mmol, 0.3 eq), 1,3-dicyclohexylcarbodiimide (64 mg, 0.31 mmol, 1.6 eq) in dichloromethane (5.0 mL) was treated with (±) cyclohexylphenylcarbinol (45 mg, 0.24 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 27 mg (26%) of L-isoleucine, N-[1-(2-(1-phenyl-1-cyclohexylmethoxy)-2-oxoethyl)-L-prolyl] benzylamide (RD-08-71, Z6338).
Reaction SMILES: N1C2C(=C([C:10]3[N:11]=[C:12]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:13]4[O:18][C:17]5[N:19]=[CH:20][C:21]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:22][C:16]=5[C:14]=4[N:15]=3)C=CC=2)C=C1.[ClH:33].FC1CCNCC1.CC([O-])=O.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH3-]C#N.[Na+]>CN(C=O)C>[Cl:33][C:10]1[N:11]=[C:12]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:13]2[O:18][C:17]3[N:19]=[CH:20][C:21]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:22][C:16]=3[C:14]=2[N:15]=1
Reactant: CN(C)Cc1cnc2oc3c(N4CCOCC4)nc(-c4cccc5[nH]ccc45)nc3c2c1
Reactant: Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: FC1CCNCC1
Solvent: CN(C)C=O
Product: CN(C)Cc1cnc2oc3c(N4CCOCC4)nc(Cl)nc3c2c1
Reaction time: 16 h
Yield: 5.6 %

Procedure:
To compound 8 (as per Example H above) (80 mg, 0.25 mmol) in dry DMF (12 mL) was added 4-fluoropiperidine hydrochloride (70 mg, 0.5 mmol) and NaOAc (41 mg, 0.5 mmol) under Ar(g). After 20 minutes NaBH(OAc)3 (106 mg, 0.5 mmol) and NaBH3CN (16 mg, 0.25 mmol) were added and the suspension was stirred for 16 h. The DMF was then removed in vacuo, EtOAc (45 mL) was added along with 50% saturated brine (7 mL), the layers separated, extracted with EtOAc (2×15 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 1-2% MeOH/CH2Cl2) furnished 9 (58 mg, 0.014 mmol, 57%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[C:13]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)[CH:14]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 482 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.30-6.85 (m, 7H), 4.90-2.70 (m, 5H), 1.90-0.65 (m, 8H).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=O)[CH2:11][C@H:10]2[C:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[O:8])=[CH:3][CH:2]=1.O.[NH2:34][NH2:35]>>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:34][NH2:35])[CH2:11][C@H:10]2[C:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: NN
Solvent: O
Product: NN=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 63 %

Procedure:
Following the general method as outlined in Example 17, starting from (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamide and hydrazine hydrate (4% in EtOH), the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (30:1) to collect the desired product, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers as a colorless solid in 63% yield (95.3% purity by HPLC).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[OH-:25].[OH-:26].[Pd+2]>C(O)C>[C:14]1([C@H:12]2[C@@H:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][N:8]([C:1]([O:26][C:11]([CH3:20])([CH3:12])[CH3:10])=[O:25])[CH2:13]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [OH-]
Reactant: CCOC(=O)C1=C(c2ccccc2)CN(Cc2ccccc2)CC1
Agent: [Pd+2]
Solvent: CCO
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 152.6 %

Procedure:
A solution of the compound (10.5 g) obtained in step 1 in 20% palladium hydroxide on carbon (50% wet, 2.63 g) in ethanol (250 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 14 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in acetonitrile (50 mL) were added triethylamine (4.6 mL) and Boc2O (7.14 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (solvent gradient; 10→20% ethyl acetate/hexane) to give 4-ethyl 1-tert-butyl (3R*,4S*)-3-phenylpiperidine-1,4-dicarboxylate (8.31 g, 76%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[C:1]1([CH:7]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([Cl:24])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(c1ccccc1)C1CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(c1ccccc1)C1CCCC1
Reaction time: 0.75 h

Procedure:
To a stirred solution of α-phenylcyclopentaneacetic acid (422 mg; 2.0 mmol) and a catalytic amount of dry dimethylformamide (ca. 20 uL) in 5 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (1.5 mL of 2.0 M solution in methylene chloride) dropwise. After 45 minutes, the mixture was concentrated in vacuo to give crude α-phenylcyclopentaneacetyl chloride which was used immediately for Step 2.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH2:22][OH:23])[CH:16]=2)=[O:14])=[N:5][C:6]([O:11][CH3:12])=[N:7][C:8]=1[O:9][CH3:10])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[C:4]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[C:19]([CH3:21])[CH:20]=2)[CH:22]=[O:23])=[O:14])=[N:5][C:6]([O:11][CH3:12])=[N:7][C:8]=1[O:9][CH3:10])[CH3:2]
Reactant: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(C=O)c1
Reaction time: 48 h
Yield: 67.4 %

Procedure:
A mixture of (5-ethyl-2,6-dimethoxy-pyrimidin-4-yl)-(3-hydroxymethyl-5-methyl-phenyl)-methanone (4.8 g, 15.2 mmol) and manganese dioxide (13.2 g, 152 mmol) in dichloromethane (110 ml) was stirred for 48 hr. at room temperature. The mixture was filtered through celite pad and the pad was washed with dichloromethane. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 3.22 g (67%) a white solid. m.p. 89-91° C.; 1H NMR (200 MHz, CDCl3) δ 1.07 (3H, t, J=7.4 Hz), 2.41-2.52 (5H, m), 3.92 (3H, s), 4.06 (3H, s), 7.91 (1H, s), 7.99 (1H, s), 8.10 (1H, s), 10.01 (1H, s).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:21][CH2:20][C@H:19]([O:22]C(=O)C2C=CC=CC=2)[C@H:11]1[C:12]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>CO>[C:3]([O:7][C:8]([N:10]1[CH2:21][CH2:20][C@H:19]([OH:22])[C@H:11]1[C:12]([NH:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)NC(=O)[C@@H]1[C@@H](OC(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
0.17 ml (0.17 mmol) of a 1N aqueous solution of sodium hydroxide was added, whilst ice-cooling, to a solution of 63 mg (0.16 mmol) of (3S)-1-t-butoxycarbonyl-3-benzoyloxy-N-t-butyl-L-prolinamide [prepared as described in step (c) above] in 1 ml of methanol and the mixture was stirred at 0° C. for 30 minutes. At the end of this time, the reaction mixture was neutralized with 1N aqueous hydrochloric acid, and the solvent was removed by distillation under reduced pressure. The resulting residue was diluted with ethyl acetate. The ethyl acetate solution was washed with a 5% w/v aqueous solution of citric acid, with a 5% aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 36 mg of the title compound as colorless crystals, melting at 122°-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([CH3:11])=[CH2:10])[CH:3]=1>C1(C)C=CC=CC=1.O=[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: C=C(C)c1cc(Br)ccc1Cl
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A mixture of 4-bromo-1-chloro-2-isopropenylbenzene (357 mg, 1.54 mmol, 1 eq) and PtO2 (35 mg, 0.15 mmol, 0.1 eq) in 4 ml toluene was stirred under an atmosphere of hydrogen at RT overnight. The reaction mixture was then filtered through celite® and the filtrate was evaporated to dryness to give the desired product (260 mg, 72%). 1H NMR (CDCl3, 300 MHz): 7.39 (d, J=2 Hz, 1H), 7.26-7.16 (m, 2H), 3.35 (sept, J=7 Hz, 1H), 1.23 (d, J=7 Hz, 6H).
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]([CH:10]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O>>[CH:1](=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:8][CH3:10]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC=O
Product: CCCCC/C=C/C=O

Procedure:
from 20 g of hexanal and 42.6 g of formylmethylenetriphenylphosphorane.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[K+].[K+].[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH3:19])[CH:13]=1>O.C(Cl)(Cl)Cl>[I:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]=[C:1]=[S:2])=[C:14]([CH3:19])[CH:13]=1
Reactant: Cc1cc(I)ccc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(I)ccc1N=C=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To a stirred mixture of 9.9 g (0.086 mole) of thiophosgene, 5.0 g (0.036 mole) of potassium carbonate in 55 ml of water and 100 ml of chloroform was added a solution of 20.0 g (0.0862 mole) of 4-iodo-2-methylaniline in 50 ml of chloroform. Additional potassium carbonate was added to make the reaction mixture basic. An additional 9.9 g of thiophosgene was added, and the reaction mixture was stirred at room temperature for approximately 18 hours. The mixture was partitioned between water (100 ml) and chloroform (100 ml). The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride to yield 22.6 g of 4-iodo-2-methylphenyl isothiocyanate as a solid, mp 51°-53° C.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5]Br.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[CH3:1][O:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CON(C)C(=O)CBr
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: CON(C)C(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The above amide (1 equiv) is dissolved in THF. Piperidine (1.1 equiv) is added and the reaction solution is stirred at ambient temperature for 48 h. The reaction mixture is concentrated and the product is purified by flash chromatography on silica using MeOH/CH2Cl2 as the mobile phase to yield N-methoxy-N-methyl-2-(piperid-1-yl)-ethanamide.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Cl:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][N:26]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)=[O:12])[CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)cc1
Yield: 94.3 %

Procedure:
Using 4-methanesulfonylaminobenzoic acid (226 mg) and 1-(3,5-dichloropyridin-2-yl)piperazine (244 mg) and by the reaction and treatment in the same manner as in Example 87, N-{4-[4-(3,5-dichloropyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (425 mg) was obtained. Using the obtained N-{4-[4-(3,5-dichloropyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (425 mg) and methylboronic acid (504 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (91 mg) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[CH:14][CH:15]=[C:5]3[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)[CH:8]=[C:9]([O:12]C)[CH:10]=2)[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[CH:14][CH:15]=[C:5]3[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH:8]=[C:9]([OH:12])[CH:10]=2)[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2ccc3cc(OC)cc1n32
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(-c2ccc(O)cc2)c2ccc3cc(O)cc1n32
Yield: 42.8 %

Procedure:
A solution of 1-ethyl-6-methoxy-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (115 mg, 0.337 mmol) in 3 ml of dichloromethane was cooled to -70° C. and 1.05 ml of a 1M boron tribromide solution in dichloromethane was added. When the addition was complete, the cooling source was removed and the mixture allowed to reach room temperature. The reaction mixture was poured into a stirred mixture of dichloromethane (125 ml) and a saturated sodium hydrogen carbonate solution (125 ml). The pH was adjusted to neutral with a 4M hydrochloric acid solution. The organic phase was separated and the aqueous phase further extracted with dichloromethane. The combined organic phases were dried and evaporated to leave 40 mg (40%) of the title compound as a semi solid substance. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.37 (t, 3H), 3.08 (q, 2H), 6.92-7.00 (m, 3H), 7.44-7.65 (m, 5H), 9.68 (s, 1H), 9.90 (s, 1H). (Compound 4).