Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH:14](OC)[O:15]C)=[CH:7][CH:8]=2)[C:3]1([CH3:20])[CH3:19]>S(=O)(=O)(O)O.O>[CH:14]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH3:13])([CH3:12])[CH2:11][CH:2]([OH:1])[C:3]2([CH3:19])[CH3:20])=[CH:8][CH:7]=1)=[O:15]
Reactant: COC(OC)c1ccc2c(c1)C(C)(C)C(O)CC2(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CC(O)C(C)(C)c2cc(C=O)ccc21
Yield: 88.9 %

Procedure:
360 g of water and 0.5 g of concentrated sulfuric acid are initially taken, and 120 g of 1,2,3,4-tetrahydro-2-hydroxy-7-dimethoxymethyl-1,1,4,4-tetramethylnaphthalene are added. The mixture is then heated to the reflux temperature and the methanol is distilled off. The organic phase is taken up with methyl tert-butyl ether. The methyl tert-butyl ether phase is separated off, the methyl tert-butyl ether is distilled off and the residue is crystallized using petroleum ether/toluene. 89 g of 7-formyl-1,2,3,4-tetrahydro-2-hydroxy-1,1,4,4-tetramethylnaphthalene (mp. 76°-78° C.) are obtained. The product obtained was characterized by 1H-NMR. 1H-NMR (250 MHz, CDCl3): δ=1.23(s,3H), 1.37(s,3H), 1.41(s,3H), 1.50(s,1H), 1.83(dd, J1 =12Hz, J2 =4Hz,1H), 1.97(t,J=12Hz,1H), 2.83(sbr.,1H), 3.95(dd,J1 =12Hz, J2 =4Hz,1H), 7.52(d,J=8Hz, 1H), 7.73(d,J=8Hz,1H), 7.97 (s,1H), 10.03(s,1H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.[NH:23]1CCC[C@H:24]1[C:25](O)=O.CCN.C([O-])([O-])=O.[K+].[K+]>O.[Cu]I.CS(C)=O>[CH2:24]([NH:23][C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1)[CH3:25]
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(Br)cn1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: CCN
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CCNc1ccc(-n2c(C(F)(F)F)nc3cc(OC)ccc32)nc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
Into a 10 ml sealed tube, was placed 1-(5-Bromo-pyridin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (30 g, 80.65 mmol). To this was added CuI (20 mg), L-Proline (20 g), CH3CH2NH2 (2 ml) and K2CO3 (30 g) followed by the addition of dimethylsulfoxide (DMSO) (6 ml). The resulting solution was allowed to stir for 6 hours at 60° C., then diluted with 10 ml of H2O and extracted two times with 30 ml of EtOAc. Organic layers were combined and washed with 20 ml of H2O. The combined organic layer was dried and concentrated, and the residue was purified by SGC using 1:12-1:6 EtOAc/petroleum ether as eluent to provide 21 g (78%) of Ethyl-[6-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyridin-3-yl]-amine (Compound 162) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=2[O:21][CH3:22])[N:10]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][CH:8]=2)=[C:14]([O:21][CH3:22])[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1OCc1coc(-c2ccco2)n1
Product: COc1cc(CCl)ccc1OCc1coc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(4-([2-(2-Furyl)-1,3-oxazol-4-yl]methoxy)-3-methoxyphenyl)methanol (5.0 g) was added to thionyl chloride (5 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-1,3-oxazole as pale-brown crystals (3.95 g, yield 74%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[N:38]=[C:37]2[C:32]([CH:33]=[C:34]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:35](=[O:39])[NH:36]2)=[CH:31][CH:30]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].Cl.[C:53]1([N:63]2[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][CH:54]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C1COCC1.ClCCCl.CCOCC>[C:53]1([N:63]2[CH2:68][CH2:67][N:66]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[N:38]=[C:37]4[C:32]([CH:33]=[C:34]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:35](=[O:39])[NH:36]4)=[CH:31][CH:30]=3)[CH2:65][CH2:64]2)[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][CH:54]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=c1[nH]c2nc(OCCCCO)ccc2cc1CC(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1[nH]c2nc(OCCCCN3CCN(c4cccc5ccccc45)CC3)ccc2cc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a suspension of Dess-Martin periodinane (0.419 g, 0.99 mmol, 1.2 eq) in CH2Cl2 (20 mL) was added a solution of 7-(4-hydroxy-butoxy)-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one (0.26 g, 0.82 mmol) in THF (8 mL). The mixture was stirred at room temperature for 1 h. Et2O (100 mL) was added to dilute the reaction mixture. The reaction was quenched with aqueous NaHCO3 (20 mL) containing Na2S2O3 (0.91 g, 5.74 mmol, 7 eq). After extraction with Et2O (3×50 mL), the combined organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated to give the crude aldehyde as a pale yellow solid. To a solution of the crude aldehyde in 1,2-dichloroethane (20 mL) was added 1-naphthalen-1-yl-piperazine monohydrochloride (0.286 g, 1.15 mmol, 1.4 eq), Et3N (0.21 mL, 1.56 mmol, 1.9 eq) and NaBH(OAc)3 (0.241 g, 1.15 mmol, 1.4 eq). The mixture was stirred at room temperature for 1 h. The reaction was quenched with water and saturated NaHCO3. After extraction with CH2Cl2 (3×50 mL), the combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (2% MeOH/CH2Cl2) to give the title compound (200 mg, 50% in two steps). 1H NMR (400 MHz, δ ppm): 9.05 (br s, 1H), 8.20 (d, J=6.2 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H), 7.75 (m, 2H), 7.58 (d, J=6.3 Hz, 1H), 7.50 (m, 2H), 7.40 (t, J=6.3 Hz, 1H), 7.10 (d, J=5.3 Hz, 1H), 6.40 (d, J=6.5 Hz, 1H), 4.40 (t, J=4.2 Hz, 2H), 3.50 (q, J=7.5 Hz, 2H), 3.20 (br s, 4H), 2.80 (br s, 4H), 2.60 (m, 2H), 1.90 (m, 2H), 1.72 (m, 2H). 19F NMR: −65.6 ppm. MS: 511 (M+). Elemental Analysis calculated for C28H29F3N4O2: C, 65.88; H, 5.69; N, 10.98. Found: C, 66.08; H, 5.89; N, 10.67.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:15])[C:11]2=O)=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:6]=1[O:26][CH3:27])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1.CCCCCC>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:6]=1[O:26][CH3:27])[CH2:9][C:10]([CH3:15])=[CH:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)CC(C)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)CC(C)=C2
Temperature: 5 °C
Reaction time: 7 h
Yield: 86.2 %

Procedure:
To a solution of 28.9 g (79.2 mmol) of 6-tert-butyl-4-(4-tert-butylphenyl)-5-methoxy-2-methylindan-1-one in 400 ml of THF cooled to 5° C. 5.00 g (132 mmol) of NaBH4 was added. Further on, 100 ml of methanol was added dropwise to this mixture by vigorous stirring for ca. 7 h at 5° C. The resulting mixture was evaporated to dryness, and the residue wad partitioned between 500 ml of dichloromethane and 1000 ml of 0.5 M HCl. The organic layer was separated, the aqueous layer was additionally extracted with 100 ml of dichloromethane. The combined organic extract was evaporated to dryness to give a colorless oil. To a solution of this oil in 500 ml of toluene 1.0 g of TsOH was added. The formed mixture was refluxed with Dean-Stark head for 15 min and then cooled to room temperature using water bath. The resulting reddish solution was washed by 10% aqueous Na2CO3, the organic layer was separated, the aqueous layer was extracted with 2×100 ml of dichloromethane. The combined organic extract was dried over K2CO3 and then passed through short pad of silica gel 60 (40-63 um). The silica gel pad was additionally washed by 50 ml of dichloromethane. The combined organic elute was evaporated to dryness to give a yellowish crystalline mass. The product was isolated by re-crystallization of this mass from 150 ml of hot n-hexane. Crystals precipitated at 5° C. were collected dried in vacuum. This procedure gave 23.8 g of white macrocrystalline 5-tert-butyl-7-(4-tert-butylphenyl)-6-methoxy-2-methyl-1H-indene. The mother liquor was evaporated to dryness and the residue was recrystallized from 20 ml of hot n-hexane in the same way. This procedure gave additional 2.28 g of the product. Thus, the total yield of the title product was 26.1 g (95%).
Reaction SMILES: C(OC([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]1OCC)=O)C.Cl.Cl.N[C@@H](CC(C)C)[C@H:23](C1C=CC=CN=1)[OH:24].C(N(CC)CC)C>ClCCl>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:15]=1[CH:14]([CH2:13][CH2:12][CH3:11])[CH2:23][OH:24]
Reactant: CC(C)C[C@H](N)[C@@H](O)c1ccccn1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CO)c1ccccn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 3.32 g sample of (S) 2-tert-butoxycarbonyl-amino-4-methyl-(R)1-(2-pyridinyl)pentan-1-ol, 0-acetate was dissolved in a mixture of 3 ml of methanol and 8 ml of 5N sodium hydroxide. The solution was stirred at 10° C. for 2 hours and then extracted with dichloromethane. The extract was dried (Na2SO4) and the solvent removed under vacuum to give 2.69 g of (S) 2-tert-butoxycarbonylamino-4-methyl-(R)1-(2-pyridinyl)-pentan-1-ol as an oil. To the preceding compound (2.69 g) was added 15 ml of 2N anhydrous hydrochloric acid in ethyl acetate. After stirring at room temperature, the solvent was removed under vacuum to give 2.46 g of (S) 2-amino-4-methyl-(R)1-(2-pyridinyl)-pentan-1-ol, dihydrochloride as tan crystals, mp 152°-154° C. To a solution of N-[(phenylmethoxy)carbonyl]-L-phenylalanyl-D,L-2-ethoxyglycine (2.0 g; 5 mmol) (Reference Example 12) and 5 mmol of 2-ethoxy- 1(2H)-quinolinecarboxylic acid ethyl ester in 50 ml of dichloromethane is added 5 mmol of (S)-2-amino-4-methyl-(R)1-(2-pyridinyl)pentan-1-ol, dihydrochlorde and 4 ml of triethylamine in 25 ml of dichloromethane. The mixture is stirred at room temperature for 20 hours and worked-up as described for Reference Example 8 to give N-[N-[(phenylmethoxy)carbonyl)-L-phenylalanyl-D,L-2-ethoxyglycyl]-(S)2-amino-4-methyl-(R)1-(2-pyridinyl pentan-1-ol as a solid.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4]/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]\1=2.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[OH:1][CH:2]([CH2:15][N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH2:3][O:4]/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]\1=2
Reactant: c1cc2c(s1)CCC/C2=N\OCC1CO1
Reactant: CN1CCNCC1
Product: CN1CCN(CC(O)CO/N=C2\CCCc3sccc32)CC1
Yield: 66 %

Procedure:
This compound is prepared by the procedure described in Example 1 by condensing E-4-(2,3-epoxypropoxy)imino-4,5,6,7-tetrahydrobenzo[b]thiophene with 1-methylpiperazine. Dioxalate: white crystals; m.p. 198° C. (recrystallised from methanol/water); yield: 66% of theory.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[F:18])[C:10]1[N:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[N:15]=[N:14][N:13]([CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[F:18])[C:8]=2[N:9]=1
Reactant: Fc1ccccc1CBr
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1CN(Cc1ccccc1F)c1nc(-c2ccco2)c2nnn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (101 mg, 0.5 mmol) in DMF (2 mL), at 0° C., was treated with NaH (20 mg, 60%, 0.5 mmol), stirred for 20 mins then treated with 2-fluorobenzyl bromide (60 μL, 0.5 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 1 h, quenched with water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (EtOAc:Heptane, 1:4-EtOAc:Heptane, 2:1) to give N,N-bis(2-fluorobenzyl)-3-(2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (Example 2) (28 mg, 11%) as a yellow solid and the title compound (34 mg, 22%) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[N:9][CH:10]=1>C(O)C>[F:18][C:4]([F:3])([F:19])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[OH:17])=[N:9][CH:10]=1
Reactant: O=C1CCCC1Cc1ccc(C(F)(F)F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCC1Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (0.036 g, 0.954 mmol) was added to a solution of 2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-one (0.116 g, 0.48 mmol) in ethanol (5 ml). The reaction was stirred at room temperature for 1 hour and then quenched with water (5 ml) and 2M HCl (aq, 5 ml), basified with 2M NaOH (aq) and extracted with ethyl acetate (2×30 ml). The combined organics were dried over dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-30% ethyl acetate/petrol) to afford the title compound as two diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.FC(F)(F)C(O)=O.[C:19]([N:26]1[CH2:30][CH2:29][C:28](=O)[CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][CH:29]3[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:30]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Nc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cnccc23)C1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
A 5 L flask (Flask A) equipped with a mechanical stirrer, internal temperature probe and addition funnel was charged with 5-aminoisoquinoline (300 g, 2.08 mol) and 2.7 L of tetrahydrofuran. Trifluoroacetic acid (543 mL, 7.29 mol) was added slowly while maintaining an internal temperature of <32° C. 1-Boc-3-pyrrolidinone (462.5 g, 2.50 mol) was added and the mixture was stirred for 10-30 minutes. A separate 12 L flask (Flask B) equipped with an internal temperature probe, mechanical stirrer and nitrogen inlet was flushed with nitrogen and charged with sodium triacetoxyborohydride (662.5 g, 3.13 mol) and 1.5 L of tetrahydrofuran. The contents of Flask A were slowly transferred to Flask B while maintaining an internal temperature in Flask B of <32° C. The reaction was stirred at 20-32° C. for 6 hours and all 5-aminoisoquinoline was consumed. The reaction was quenched with 3 L of 5N NaOH maintaining a temperature of <45° C. After 20 minutes, the aqueous layer was separated. The organic phase was washed with 3 L of 2N NaOH at 40° C. (with external heating). The organic phase was diluted with isopropyl acetate (2.25 L), washed with 1.5 L of water at 40° C. (with external heating), and concentrated to ˜2 L by distillation. The resulting solution was cooled to ˜20° C. The resulting slurry was filtered, washed (3×200 mL of MTBE), and dried in a vacuum oven at ˜60° C. Approximately 536 g of tert-Butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate was isolated as a solid (82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13]>>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:30]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C
Yield: 26 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([F:22])[CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1CCC(C(O)c2ccc(Br)cc2)C1
Solvent: ClCCl
Product: CN1CCC(C(F)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Cool a solution of (4-bromo-phenyl)-(1-methyl-pyrrolidin-3-yl)-methanol in CH2Cl2 (6.5 mL) to 0° C. Add slowly a solution of DAST (0.1 mL, 0.78 mmol) in CH2Cl2. Stir the mixture at RT overnight. Cool the mixture to 0° C., then carefully quench with saturated NaHCO3 (exothermic and gas evolution). Extract the aqueous layer with CH2Cl2. Dry the combined organic phases with Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, collecting all the fractions as the product does not show by UV. Elute with 5-10% MeOH (2 N NH3)/CH2Cl2 to give 0.049 g (35%) of the title compound. LC-MS/ES m/z (79Br) 272.0 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:22]1[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(O)c1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
CBz-L-valine (10 g, 40 mmol), 1,3-dihydroxybenzene (8.7 g, 79 mmol) N,N′dicychlohexylcarbodiimide (10.2 g, 44 mmol) and 4-dimethylaminopyridine (2.4 g, 20 mmol) were dissolved in DMF (50 ml) and left at ambient temperature overnight. The reaction mixture was filtered, the solvent removed under reduced pressure and the crude product was taken up in dichloromethane and filtered. Removal of the solvent followed by purification by chromatography (chloroform—methanol, 10:1) yielded pure title product (10.9 g, 79%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](N2C(C)=CC=C2C)=[C:7]([N+:18]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCO[C:24]([CH3:26])=O>[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[C:7]([CH3:8])[NH:18][C:24]=2[CH3:26])=[C:7]([CH:6]=1)[NH2:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C)n1-c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2N)c(C)[nH]1
Yield: 99 %

Procedure:
A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd/C (0.056 g) and EtOAc (50 mL) under an H2 atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) Rf 0.43; 1H NMR (CDCl3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:10][C:3]=12
Reactant: COc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3nccc(Cl)c3s2)cn1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
To a solution of tributyltin derivative 6 (2.00 g, 4.36 mmol) (scheme 91) in toluene (10 mL) was added Ph(PPh3)4 (0.503 g, 0.436 mmol) followed by 5-bromo-2-methoxypyridine (0.62 mL, 4.8 mmol). Nitrogen gas was bubbled directly into the reaction mixture for 30 minutes before it was heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and the yellow precipitate was collected by filtration and washed with hexanes. The material was then further purified by flash chromatography (eluent 20 to 50% ethyl acetate in hexanes) to afford the titled compound 418 as a fluffy white solid (0.752 g, 62% yield). MS (m/z): 277.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][N:40]3[C:44](=[O:45])[CH2:43][CH2:42][C:41]3=[O:46])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1O
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 93.1 %

Procedure:
Following a procedure similar to that described in Example 52(a), but using 600 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)imidazole-5-carboxylic acid [prepared as described in step (c) above], 172 mg of N-hydroxysuccinimide and 250 mg of N,N-dicyclohexylcarbodiimide, 663 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH:15]1([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:2]([NH:24][NH2:25])=[N:3][CH:4]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NN
Reactant: O=C(Nc1ccc(C2CCCCC2)cc1)c1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)Nc2ccc(C3CCCCC3)cc2)cn1
Yield: 99 %

Procedure:
6-Chloro-N-(4-cyclohexylphenyl)nicotinamide (0.40 g) and hydrazine monohydrate (3 mL) were suspended in ethanol (6 mL), and the suspension was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was then collected by filtration and washed with an ethyl acetate-ethanol mixed solvent. The solid was dried under reduced pressure to obtain the title compound (0.39 g) as a white solid (yield: 99%).