Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1)#[N:23]>>[C:22]([C:24]1([C:27]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:21][CH:20]=2)=[O:28])[CH2:26][CH2:25]1)#[N:23]
Reactant: Nc1ccc(CCCCCCCCc2ccccc2)cc1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCCc3ccccc3)cc2)CC1
Yield: 98.4 %

Procedure:
General procedure E was used to convert 3.15 mmol of 17a and 4.73 mmol of 1-cyanocyclopropanecarboxylic acid to 3.10 mmol (98%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([CH3:28])=[N:10][C:11]2[N:12]([CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.CCN(CC)CC.[BH4-].[Na+]>C1COCC1.O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:12]2[CH:22]=[C:23]([CH2:25][OH:26])[N:24]=[C:11]2[N:10]=[C:9]([CH3:28])[C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc2nc(CO)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 103.1 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (400 mg, 0.95 mmol) in THF (6 mL) at room temperature was added ClCOOEt (0.14 mL, 1.42 mmol) and Et3N (0.26 mL, 1.9 mmol). After 1.5 h, the reaction was filtered to remove the insolubles and to the filtrate at 0° C. was added NaBH4 (72 mg, 1.9 mmol) in H2O (0.2 mL). After 30 min, the reaction was quenched with 1N HCl and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration and concentration under reduced pressure afforded the crude tert-butyl 5-(2,4-dichlorophenyl)-2-(hydroxymethyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (400 mg, 100% crude yield) which was moved on to next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17](NCCC3C=CC(OCC(OCC)=O)=C(OCC(OCC)=O)C=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=C[CH:48]=1>ClCCl>[C:17]([C:15]1[S:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=2[CH:16]=1)(=[O:18])[CH3:48]
Reactant: c1cc[nH+]cc1
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1OCC(=O)OCC
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.67 h
Yield: 191.3 %

Procedure:
To the solution of the compound prepared in (a) (847 mg) in dichloromethane (30 ml) was added Molecular Sieves 4A (3 g), followed by pyridinium chlorochromate (966 mg) under ice-cooling. The mixture was stirred for 40 minutes. After the reaction mixture was filtered through FLORISIL, the filtrate was concentrated to give 772 mg of 2-acetyl-5-t-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (yield, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[NH:16][C:15](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:14][N:13]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][CH2:10][CH2:9][CH:8]([C:12]1[NH:16][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)=[N:14][N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COc1cc(/C=C/c2nnc(C(CCO)c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nnc(C(CCCl)c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A solution of 3-(4-fluorophenyl)-3-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}propan-1-ol (83 mg) in phosphorus oxychloride (1 mL) was stirred at 120° C. for one hour. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 86 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:1]([C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2c(c1)Cc1ccccc1O2
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)Cc1ccccc1O2
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of 2-hydroxy-9H-xanthene 3 (2.63 g, 13.28 mmole) in DMF (15 ml) was added imidazole (1.36 g, 19.9 mmole), t-butyldimethylsilyl chloride (2.4 g, 15.92 mmole) and DMAP (15 mg) successively at room temperature. The mixture was allowed to stir overnight (16 hrs) and quenched with saturated NaHCO3 solution. The aqueous layer was extracted two times with 10% EtOAc-hexanes. The combined organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated. The light orange oily residue was loaded onto a silica gel plug and eluted with hexanes and then 3% EtOAc-hexanes. The relatively clean fractions of the desired product were pooled and concentrated, yielding the slightly impure 2-tert-butyldimethylsiloxyl-9H-xanthene 4 (3.297 g, 79.5%) as an off-white solid: mp 67-69° C. 1H NMR (CDCl3): delta 7.12-7.19 (2H, m), 6.96-7.01 (2H, m), 6.89 (1H, d, J=8.5 Hz), 6.61-6.67 (2H, m), 3.98 (2H, s), 0.97 (9H, s) and 0.17 (6H, s); 1R (CHCl3): 2960, 2938, 1630, 1587, 1487, 1464, 1251, 1203, 1158, 1120, 976, 892, 868 and 843 cm-1.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2F)C1
Yield: 72.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-fluorophenylboronic acid (128 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (150 mg, 72.1%) as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH2:18][CH3:19])[C:8]2[CH:20]=[CH:21][CH:22]=[CH:23][C:7]1=2)=[O:5].[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>C(O)(C)C>[ClH:1].[CH2:18]([N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]([C:4](=[O:5])[CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]2[CH3:24])[C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]1=2)[CH3:19]
Reactant: CCN1C(=O)c2ccccc2N(C(=O)CCCl)c2ccccc21
Reactant: CC1CCCCN1
Solvent: CC(C)O
Product: CCN1C(=O)c2ccccc2N(C(=O)CCN2CCCCC2C)c2ccccc21
Product: Cl

Procedure:
6.6 gm (0.02 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-10-ethyl-11H-dibenzo[b,e][1,4]diazepin-11-one (m.p. 133°-134° C.) and 5 gm (0.05 mol) of 2-methyl-piperidine were refluxed in 100 ml of isopropanol for 2 hours. The reaction mixture was evaporated in vacuo, the residue was dissolved in methylene chloride, and the solution was washed with water. After evaporation of the solvent, the residue was dissolved in hot acetone, and the calculated amount of hydrochloric acid was added.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[OH:27])C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)[O:53][CH2:52][CH:51](O)[CH2:50][O:49]1.CC[O:58][C:59](/N=N/C(OCC)=O)=[O:60]>C1COCC1.C1(C)C=CC=CC=1>[CH2:24]([N:22]([CH2:21][C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:8]=[C:3]([CH3:1])[C:4]([O:27][CH:51]([CH2:52][OH:53])[CH2:50][OH:49])=[C:5]([CH3:26])[CH:6]=3)[N:13]=2)[CH:19]=[C:18]([CH3:20])[CH:17]=1)[CH3:23])[CH3:25].[CH:59]([O-:60])=[O:58]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CC1(C)OCC(O)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(C)Cc1cc(C)cc(-c2nc(-c3cc(C)c(OC(CO)CO)c(C)c3)no2)c1
Product: O=C[O-]
Reaction time: 16 h

Procedure:
To a solution of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (100 mg, 273 μmol) in THF (2 mL), PPh3 (107 mg, 409 μmol) followed by 2,2-dimethyl-[1,3]dioxan-5-ol (54 mg, 409 μmol) was added. The mixture was stirred at 0° C. for 10 min before DEAD (178 mg, 409 μmol, 188 μL of a 40% solution in toluene) was added. Stirring was continued at rt for 16 h. Another portion of PPh3 (107 mg, 409 μmol) and DEAD (178 mg, 409 μmol) was added and the mixture was stirred at rt for another hour. The solvent was removed in vacuo and the residue was dissolved in MeCN and separated by prep. HPLC. The acetal intermediate containing fractions were combined and concentrated. The residue was dissolved in MeCN (0.5 mL) and 1N aq. HCl (0.4 mL) and allowed to stand at rt for 10 min before it was again purified by prep. HPLC to give the title compound as a formate salt in the form of a white lyophilisate (71 mg). LC-MS: tR=0.55 min; [M+1]+=440.22; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.21 (t, J=7.5 Hz, 3H), 2.15 (s, 3H), 2.37 (s, 3H), 2.42-2.48 (m, 5H), 2.78 (q, J=7.5 Hz, 2H), 3.56 (s, 2H), 3.60 (dd, J=11.5 Hz, 5.3 Hz, 2H), 3.64 (dd, J=11.5, 5.0 Hz, 2H), 3.98 (quint, J=5.3 Hz, 1H), 4.77 (br s, 1H), 7.47 (s, 1H), 7.76-7.79 (m, 2H), 7.90 (s, 1H), 7.93 (s, 1H), 8.18 (s, 1H, formate).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)=[CH:2]1.[CH2:22]([Zn]CC)C.ICI>C(Cl)Cl.CCCCCC>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]23[CH2:22][CH:14]2[CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ncccc23)C1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC2(c2c[nH]c3ncccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (700 mg, 2.5 mmol) in DCM (20 mL), was added dropwise at 0° C. under nitrogen atmosphere diethylzinc (6.13 mL of a 1M solution in hexane, 6.1 mmol) and diiodomethane (0.79 mL, 9.8 mmol). The mixture was warmed to RT and stirred at RT overnight. The mixture was then cooled with an ice bath and quenched with a saturated aqueous solution of ammonium chloride. The mixture was extracted with DCM, dried over sodium sulphate and concentrated in vacuo. The residue was triturated in diisopropylether and the resulting precipitate was filtered and then purified by column chromatography (DCM/MeOH 95:5) to afford the title compound as a yellow solid (100 mg).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([O:15]C(=O)C)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:19]Br>C(O)(=O)C>[BrH:19].[Br:19][CH2:2][C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([OH:15])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)c1nc(C(C)=O)ccc1OC(C)=O
Solvent: CC(=O)O
Product: Br
Product: CCOC(=O)c1nc(C(=O)CBr)ccc1O
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.88 g of 6-acetyl-3-acetyloxy-2-ethoxycarbonylpyridine in 8.8-ml of acetic acid was added 0.19 ml of bromine dropwise, and the mixture was stirred at 75° C. for 5 minutes. Evaporation of the solvent gave 0.77 g of 6-(2-bromoacetyl)-2-ethoxycarbonyl-3-hydroxypyridine hydrobromide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)NC
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
(2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.14 g; 0.54 mmol)(prepared as in example 33) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.07 g; 0.54 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl)propionamide (0.21; 0.54 mmol) was dissolved in methylene chloride (10 mL) and added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (10 mL) was added. The reaction mixture was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 20 mL) and an aqueous solution of sodium hydrogen carbonate (saturated; 20 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×20 cm) using methylene chloride/ethyl acetate (1:1) as eluent to afford 0.27 g of (1,1-dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamoyl)methoxy)ethyl)carbamic acid tert butylester.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[OH:15].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:15][C:3]1[CH:4]=[C:5]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccccc2)cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
This is obtained, by reacting 2-methyl-3-nitro-5-tert.-butylphenol with benzyl chloride in dimethylformamide in the presence of potassium carbonate at 80° C., in the form of yellowish crystals; m.p. 77°-79° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1)=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1.Cl>CN(C=O)C.O>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([C:25](=[N:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[C:36]([CH3:38])[O:35][N:34]=3)=[CH:29][CH:28]=2)[C:24]2[NH:23][C:22](=[O:21])[N:2]([C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]([OH:8])=[O:7])[N:3]=2)[CH:44]=[CH:43][C:42]=1[O:45][CH3:46]
Reactant: NNc1ccccc1C(=O)O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 90 °C
Reaction time: 20 h
Yield: 32.3 %

Procedure:
After adding 38 mg of 2-hydrazinobenzoic acid hydrochloride and 0.056 ml of triethylamine to a solution of 91 mg of [2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 5 ml of DMF, the mixture was stirred at 90° C. for 20 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 30 ml of water was added, hydrochloric acid was added (for adjustment to pH 3-4), and extraction was performed with 50 ml of ethyl acetate. The organic layer was washed twice with 30 ml of water and once with 30 ml of saturated brine, and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-dichloromethane) to give the title compound (34 mg) as a light yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CS(C)=O>C(OCC)(=O)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: C[C@H](N)c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(I)ccn1)c1ccccc1
Temperature: 25 °C

Procedure:
The mixture of 1 g of 2-fluoro-4-iodopyridine (synthesized according to a method disclosed in J. Org. Chem. 1993, 58, 7832-7838), 1.73 mL of (1S)-1-phenylethylamine, and 20 mL of dimethylsulfoxide, was stirred overnight at 80° C. The reaction mixture was cooled back to room temperature, then diluted with ethyl acetate, and washed with water and saturated brine in the subsequent order. The obtained organic layer was dried over anhydrous magnesium sulfate, then the insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by silica gel column chromatography, to obtain 744 mg of 4-iodo-N-[(1S)-1-phenylethyl]-2-pyridinamine [58-1] as a light brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[NH:6][CH:7]=1)=[O:2].[I:12]I>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[NH:6][C:7]=1[I:12])=[O:2]
Reactant: COC(=O)c1cc(C=O)c[nH]1
Reactant: II
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C=O)c(I)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3 (3.40 g, 22.2 mmol) in CHCl3 (20 mL) at 0° C. was added CF3CO2Ag (5.40 g, 24.4 mmol) followed by I2 (3.10 g, 24.4 mmol). The resulting mixture was stirred for 16 hours in the dark at room temperature. The reaction mixture was filtered through Celite and the filtrate was washed with saturated aqueous solution of Na2S2O3 (2×20 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. MPLC purification (CH2Cl2:diethyl ether/95:5) of the residue gave 4 as a white solid (0.72 g, 32% based on the recovered starting material). Along with 4, two minor compounds methyl 4-formyl-5-iodo-1H-pyrrole-2-carboxylate, methyl 4-formyl-3,5-diiodo-1H-pyrrole-2-carboxylate and the starting material 3 were also isolated. 1H NMR (400 MHz, DMSO-d6) δ 13.30 (brs, 1H), 9.52 (s, 1H), 7.04 (s, 1H), and 3.77 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 187.13, 160.36, 128.78, 127.79, 115.58, 87.40, and 52.42.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:19])=[O:18]
Reactant: OCCc1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccsc1

Procedure:
The 2-(3-thienyl)ethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C1(C)C=CC=CC=1.[CH3:19][C:20]1([C:35](OCC)=[O:36])[CH2:25][CH2:24][CH2:23][N:22]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:21]1>C(Cl)Cl>[CH:1]1([NH:7][C:35]([C:20]2([CH3:19])[CH2:25][CH2:24][CH2:23][N:22]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH2:21]2)=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(C)CCCN(S(=O)(=O)c2ccccc2)C1
Reactant: NC1CCCCC1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1(C(=O)NC2CCCCC2)CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.2 %

Procedure:
At r.t., to a solution of cyclohexanamine (19.1 mg, 0.19 mmol) in methylene chloride (0.1 mL) was added 2.0 M of trimethylaluminum in toluene (96 ul, 0.19 mmol). After stirring for 30 min, to the solution was added a solution of ethyl 3-methyl-1-(phenylsulfonyl)piperidine-3-carboxylate (35 mg, 0.11 mmol) in methylene chloride (0.1 mL). The mixture was stirred at r.t for 10 min, then, at 40° C. overnight. After cooling to r.t., the mixture was purified with combi-flash. The product was further purified with prep. HPLC. 1.3 mg final product was obtained. Yield: 3.2%. LCMS: m/z 365.1 (M+H)+; 751.3 (2M+Na)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[CH2:12]([O:14][C:15](=[O:31])/[CH:16]=[C:17](/[O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[CH3:30])\[CH2:18]Br)[CH3:13].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][CH2:18]/[C:17](/[O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[CH3:30])=[CH:16]\[C:15]([O:14][CH2:12][CH3:13])=[O:31])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc2c1cnn2C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)/C=C(\CN[C@@H](CC(C)C)C(=O)OC)Oc1cccc2c1cnn2C
Temperature: 90 °C
Yield: 62 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.043 g, 0.24 mmol), (E)-4-bromo-3-(1-methyl-1H-indazol-4-yloxy)-but-2-enoic acid ethyl ester (0.073 g, 0.22 mmol) and N,N-diisopropylethylamine (0.070 g, 0.54 mmol) in acetonitrile (6 mL) in a sealed tube was heated at 90° C. for 18 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 100% diethyl ether/hexanes) to afford (S)-2-[(E)-3-ethoxycarbonyl-2-(1-methyl-1H-indazol-4-yloxy)-allylamino]-4-methyl-pentanoic acid methyl ester (0.055 g, 66%).