Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH3:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N([CH2:30][CH3:31])C(C)C)(C)C>C(OCC)(=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:13]([CH2:7][C:6]([O:15][CH2:30][CH3:31])=[O:5])[C:10]1[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:8][C:9]=1[CH3:14])[CH3:22]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1N
Reactant: CCOC(=O)CBr
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC(=O)OCC)c1ccc(C(=O)OC(C)(C)C)cc1C
Temperature: 140 °C

Procedure:
The compound (51.5 g) obtained in step B, ethyl bromoacetate (160 ml, 1.44 mol) and N,N-diisopropylethylamine (250 ml, 1.47 mol) were mixed, and the mixture was stirred with heating at 140° C. for 10 hr. The reaction mixture was cooled, diluted with ethyl acetate, and the organic layer was washed with 20% aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give a mixture of the title compound and N-(4-tert-butoxycarbonyl-2-methyl)phenylglycine ethyl ester. To this mixture were added ethyl bromoacetate (80 ml, 719 mmol) and N,N-diisopropylethylamine (125 ml, 735 mmol), and the mixture was stirred again with heating at 140° C. for 11 hr, which was followed by the purification similar to the above to give the title compound (95.3 g) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:10])[CH:3]=[CH:2]1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:10][S:18]([CH3:17])(=[O:20])=[O:19])[CH:3]=[CH:2]1
Reactant: Nc1cccc2cc[nH]c12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc2cc[nH]c12
Yield: 94 %

Procedure:
Stir 1H-indol-7-ylamine with pyridine (1 equivalent) and methanesulfonyl chloride (1 equivalent) in dichloromethane for 12 hrs. Wash the reaction with 1N hydrochloric acid and water, dry over magnesium sulfate, and evaporate. Recrystallize the residue from isopropanol to obtain the title product as a purple solid (94%). MS (ES+), 210 (M), MS (ES−), 209 (M−1). LC/MS shows 95% purity.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:28]=[CH:29][CH:30]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:34]>C(O)C>[Na+:34].[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[C:21]([C:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:28]=[CH:29][CH:30]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1cccn1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1cccn1C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of the methyl 10-(4-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylate of Example 1, Step C (0.200 g) in anhydrous ethanol (2 mL) was added 2.5 N sodium hydroxide (1 equiv.). The reaction mixture was stirred for three days at room temperature and the solvent removed in vacuo to provide the title compound as a pale-yellow hygroscopic solid after drying over phosphorus pentoxide at 60° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C@@H:3]([CH3:5])[OH:4].Cl.CCN(C(C)C)C(C)C.[NH:23]([C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[C@H:24]([C:32](O)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)CCl>C(Cl)Cl>[NH:23]([C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[C@H:24]([C:32]([NH:1][C@H:2]([C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@H](O)[C@H](N)C(=O)OC(C)(C)C
Reactant: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)O
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
H-Thr-OtBu-HCl (3.1 g, 15 mmol, 1.3 equiv) was dissolved in CH2Cl2 (30 mL) and DIEA (2.9 mL, 17 mmol, 1.5 equiv) was added and the mixture allowed to stir for 30 min. Alloc-Phe-OH (2.8 g, 11 mmol, 1 equiv) and EDC (2.8 g, 15 mmol, 1.3 equiv) in CH2Cl2 (35 mL) was then added and the reaction was stirred for 18 h. The organic reaction mixture was washed with H2O (3×25 mL), dried (MgSO4) and concentrated in vacuo. The resultant oil (4.12 g) was purified by flash chromatography [CHCl3-MeOH—HOAc (9:1:0.2)] to give the title product (3.25 g, 8 mmol, 71% yield), which was characterized by analytical HPLC (tR 20.9 min, >98% purity; Condition C); ESMS, calcd for C21H30N2O6, 406.2. Found: m/z 408.0 [M+H]+; 1H-NMR (200 MHz, CDCl3): 7.1-7.3 (5H, m, Ar); 6.89 (1H, d, J=8.8 Hz, NH); 5.7-5.9 (1H, m, CH allyl); 5.56 (1H, d, J=8.0 Hz, OH); 5.2-5.3 (2H, m, CH2 g-allyl); 4.52 (2H, d, J=5.4 Hz, CH2 a-allyl); 4.45 (1H, dd, J=8.4 Hz, 2.8 Hz, a-CH Thr); 4.22 (1H, dq, J=6.2 Hz, J=3.0 Hz, b-CH Thr); 3.0-3.2 (2H, m, b-CH2 Phe); 1.47 (9H, s, tBu); 1.15 (3H, d, J=6.6 Hz, g-CH3 Thr); 13C-NMR (50 MHz, CDCl3): 172.2 (CO), 169.5 (CO); 156.0 (CO); 136.1 (Cq, Ar); 132.5 (CH, allyl); 129.3 (CH, Ar); 128.5 (CH, Ar); 126.9 (CH, Ar); 117.7 (CH2, allyl); 82.7 (Cq, tBu); 68.5 (b-CH Thr); 65.9 (CH2, allyl); 58.0 (a-CH Thr); 56.2 (a-CH Phe); 38.3 (b-CH2 Phe); 28.0 (CH3, tBu); 20.8 (g-CH3 Thr).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[C:35]([OH:40])[CH:34]=2>CN(C=O)C>[F:29][C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[C:35]([O:40][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)[CH:34]=2
Reactant: Oc1ccc2cc(F)cnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc(F)cnc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (218 mg, 0.68 mmol), (prepared as described for the starting material in Example 9), potassium carbonate (138 mg, 1.13 mmol) and 3-fluoro-7-hydroxyquinoline (117 mg, 0.72 mmol), (prepared as described for the starting material in Example 157), in DMF (4.5 ml) was stirred at 100° C. for 4 hours and then allowed to cool to ambient temperature. The reaction mixture was evaporated to dryness and the residue taken up in dichloromethane, washed with water, brine and dried (MgSO4). The organic fractions were evaporated to dryness and the residue recrystallised from acetonitrile to give 4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (86 mg, 28%).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7]/[C:8](/[C:16]([O:18][CH3:19])=[O:17])=[CH:9]\[C:10]1[O:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(C)(C)C>FC(F)(F)C(O)=O.O.C1(C)C=CC=CC=1>[CH3:19][O:18][C:16](/[C:8](=[CH:9]/[C:10]1[O:11][C:12]([CH3:15])=[CH:13][CH:14]=1)/[CH2:7][C:6]([OH:20])=[O:5])=[O:17]
Reactant: COC(=O)/C(=C/c1ccc(C)o1)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)/C(=C/c1ccc(C)o1)CC(=O)O
Yield: 94.4 %

Procedure:
A solution of E-3-methoxycarbonyl-4-(5-methylfur-2-yl)-but-3-enoic acid t-butyl ester (Method 16; 1.39 g, 4.96 mmol) in trifluoroacetic acid/water (20 ml of 90:10 v/v) was stirred at ambient temperature for 20 mins; the reaction mixture was then diluted with toluene (30 ml) and evaporated in vacuo to yield a brown oil. After further azeotroping with toluene (30 ml), this set solid; trituration with isohexane and collection of the residue yielded the title compound as a brown solid (1.05 g, 95%). NMR 2.33 (s, 3H), 3.65 (s, 2H), 3.72 (s, 3H), 6.29 (d, 1H), 6.85 (d, 1H), 7.41 (s, 1H), 12.34 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1>CNCCCC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:8]([CH2:7][CH2:6][CH2:5][CH3:4])[CH3:9])=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Agent: CCCCNC
Product: CCCCN(C)c1nccc2ccc(Br)cc12
Yield: 161.1 %

Procedure:
A solution of 7-bromo-1-chloroisoquinoline (750 mg, 3.09 mmol) in N-methylbutylamine (7.0 mL) was heated at 65° C. in a sealed tube for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with chloroform and washed with saturated sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield a brown oil. Purification by flash column chromatography (silica, 3:1 hexanes/diethyl ether) provided 7-bromo-N-butyl-N-methylisoquinolin-1-amine (730 mg): ESI MS m/z 293 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9]([OH:11])=O)[CH3:4])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:58]([O:65][C:66]1[C:75]([CH3:76])=[CH:74][C:69]([C:70]([NH:72][NH2:73])=O)=[CH:68][C:67]=1[CH2:77][CH3:78])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CC(=O)OCC>[CH2:58]([O:65][C:66]1[C:75]([CH3:76])=[CH:74][C:69]([C:70]2[O:11][C:9]([C:8]3[CH:7]=[C:6]([CH:14]=[C:13]([CH3:15])[CH:12]=3)[CH2:5][N:3]([CH2:1][CH3:2])[CH3:4])=[N:73][N:72]=2)=[CH:68][C:67]=1[CH2:77][CH3:78])[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: CCN(C)Cc1cc(C)cc(C(=O)O)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3cc(C)cc(CN(C)CC)c3)o2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 3-[(ethyl-methyl-amino)-methyl]-5-methyl-benzoic acid (750 mg, 3.62 mmol) in THF (10 mL), DIPEA (940 mg, 7.24 mmol) and PyBOP (1.88 g, 3.62 mmol) was added. The mixture was stirred at rt for 1 h before 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide (2.06 g, 3.62 mmol) was added. The mixture was stirred at rt for 1 h and was then diluted with EA and washed with sat. aq. NaHCO3 solution. The org. phase was collected, dried over MgSO4, filtered and concentrated. The residue was dissolved in THF and Burgess reagent (1.03 g, 4.34 mmol) was added. The mixture was stirred at 110° C. under microwave irradiation for 12 min. The mixture was cooled to rt, diluted with EA and washed with water. The org. phase was separated and concentrated. The crude product is purified by CC on silica gel eluting with DCM:MeOH 9:1 to 5:1 to give {3-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-5-methyl-benzyl}-ethyl-methyl-amine as a pale yellow oil (1.48 g). LC-MS: tR=0.96 min; [M+1]+=456.13.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[C:21]3/[C:20](=[O:22])[NH:19][C:18](=[O:23])[S:17]/3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(=O)/C(=C/c2ccc(Oc3ccc(F)cc3)cc2)S1

Procedure:
To a solution of 4-(4-fluorophenoxy)benzaldehyde (0.54 g, 2.5 mMol) and 2,4-thiazolidinedione (0.352 g, 3 mMol) in toluene (20 mL) were added piperidine (0.032 mL, 0.325 mMol) and benzoic acid (0.046 mg, 0.375 mMol). The reaction was refluxed for 4 h with continuous removal of water. The reaction was cooled and filtered. The crystalline product collected was washed with petroleum ether on the filter and dried in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2>>[OH:10][C@@H:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Product: C[C@@H](O)c1cccc(O)c1

Procedure:
3′-hydroxyacetophenone and (S)-(−)-2-methyl-CBS-oxazaborolidine were reacted as described in Example 35, Step 1 to provide 3-((R)-1-hydroxy-ethyl)-phenol.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:51][S:52]([C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1)(=[O:54])=[O:53])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:50])[C@H:31]([CH:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:32][C:33]([O:35][CH3:36])=[O:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:83](O)[CH2:84][CH:85]([CH3:87])[CH3:86].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:51]([CH2:83][CH2:84][CH:85]([CH3:87])[CH3:86])[S:52]([C:55]1[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=1)(=[O:53])=[O:54])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:50])[C@H:31]([CH:37]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[NH:32][C:33]([O:35][CH3:36])=[O:34])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCO
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A solution of N-{2-[(3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(4-nitrophenyl)sulfonyl]amino}butyl]phenyl}-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (9, 160 mg, 0.181 mmol), Ph3P (149 mg, 0.568 mmol) and isoamyl alcohol (89 mg, 1.01 mmol) (or any other suitable alcohol) in THF (1.5 ml) stirred at external temperature of 0° C. under N2 atmosphere, was treated with neat DIAD (150 μL, 0.771 mmol) and the mixture stirred at the same temperature for 30 min and then at room temperature in the dark for 16 h, concentrated and purified in a cromatographic cartridge of silicagel (24 g) eluted with 10% to 40% EtOAc in hexane, to get 143 mg (83%) of the title compound as white foam MS: m/z=955.3 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:10]2)=[N+:2]=[N-:3].[OH:23]C1C=C2C(=CC=1)OC(C1C=CC=CC=1)CC2=O>>[N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][C:10]2=[O:23])=[N+:2]=[N-:3]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(O)cc21
Reactant: [N-]=[N+]=NCCOc1ccc2c(c1)CCC(c1ccccc1)O2
Product: [N-]=[N+]=NCCOc1ccc2c(c1)C(=O)CC(c1ccccc1)O2

Procedure:
6-(2-Azidoethoxy)-2-phenylchroman-4-one was prepared as described for 6-(2-azidoethoxy)-2-phenylchroman in example 4(a) starting from 1.0 g of 6-hydroxy-flavanone. 1H NMR (400 MHz, CD3OD) δ: 7.53-7.51 (m, 2H), 7.44-7.35 (m, 4H), 7.22 (dd, 1H, J 9.0, 3.1 Hz), 7.04 (d, 1H, J 9.0 Hz), 5.51 (dd, 1H, J 13.1, 3.0 Hz), 4.17 (t, 2H, J 4.9 Hz), 3.60 (t, 2H, J 4.9 Hz), 3.11 (dd, 1H, J −16.9, 13.1 Hz), 2.85 (dd, 1H, J −16.9, 3.0 Hz).
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@@H:17]2[CH2:18][C@@H:14]([CH:15]=[CH:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20])=O)C1C=CC=CC=1.[ClH:23].O1CCOCC1>C(OCC)(=O)C.[Pd].C(OCC)C>[ClH:23].[NH2:11][C@H:12]1[C@@H:17]2[CH2:18][C@@H:14]([CH2:15][CH2:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)OCc2ccccc2)[C@H]2C=C[C@@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@@H]2CC[C@@H](C2)[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (1S,2R,3S,4R)-3-{[(benzyloxy)carbonyl]amino}bicyclo[2.2.1]hept-5-ene-2-carboxylate (5.5 g, 18.27 mmol) was dissolved in ethyl acetate (75 mL). 5% Palladium on carbon (650 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in ethyl acetate (15 mL) and added dropwise, with vigorous stirring, to a mixture of a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) in diethyl ether (90 mL). The desired product began to precipitate as a white solid. The mixture was stirred for 20 min. The precipitate was collected by vacuum filtration, and was washed with additional diethyl ether (15 mL). The solid was further dried in vacuo for 1 h to afford the desired product, methyl (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (2.61 g, 12.69 mmol, 69%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.34-1.43 (4H, m), 1.54 (1H, d, J=9.5 Hz), 1.68 (1H, d, J=11.4 Hz), 2.47-2.48 (2H, m), 3.03 (1H, dd, J1=11.0 Hz, J2=4.0 Hz), 3.49-3.53 (1H, m), 3.62 (3H, s), 8.07 (3H, bs). LC-MS (ESI) calcd for C9H15NO2 (free amine) 169.11, found 170.1 [M+H+] (100%), 339.2 [2M+H+] (50%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:16]=1[CH2:17][NH:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[C:22]([NH2:35])=[CH:21][N:20]=1>C1COCC1>[CH3:13][O:14][C:15]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:16]=1[CH2:17][NH:18][C:19]1[N:24]=[C:23]2[C:22]([NH:35][C:1](=[O:2])[N:25]2[CH2:26][C:27]2[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=2[F:33])=[CH:21][N:20]=1
Reactant: COc1ccc(CNc2ncc(N)c(NCc3c(F)cccc3F)n2)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncc3[nH]c(=O)n(Cc4c(F)cccc4F)c3n2)c(OC)c1

Procedure:
Carbonyldiimidazole (0.93 g) was added to a solution of N2-(2,4-dimethoxybenzyl)-N4-(2,6-difluorobenzyl)pyrimidine-2,4,5-triamine (54) in THF (20 mL) and the resultant mixture stirred at RT overnight, then the solvents were removed under reduced pressure and the taken up in EtOAc and washed trice with water. The organics were dried, filtered and evaporated and purified via column chromatography, elution with 2.5 and 4% MeOH/DCM, to yield 2-(2,4-Dimethoxybenzylamino)-9-(2,6-difluorobenzyl)-7H-purin-8(9H)-one (55) (0.58 g), MH+=428.
Reaction SMILES: [I-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[OH:24][C:25]1[CH:42]=[CH:41][C:40]2[C@:39]3([CH:43]=O)[C@H:30]([C@H:31]4[C@@:35]([CH2:37][CH2:38]3)([CH3:36])[CH2:34][C@H:33]([OH:45])[CH2:32]4)[CH2:29][CH2:28][C:27]=2[CH:26]=1.O>CS(C)=O>[CH:43]([C@:39]12[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][C@@H:33]([OH:45])[CH2:34]3)[C@@H:30]1[CH2:29][CH2:28][C:27]1[CH:26]=[C:25]([OH:24])[CH:42]=[CH:41][C:40]2=1)=[CH2:2]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=C[C@]12CC[C@]3(C)C[C@H](O)C[C@H]3[C@@H]1CCc1cc(O)ccc12
Reaction time: 0.17 h

Procedure:
Under inert-gas atmosphere, 3.1 g (7.9 mmol) of triphenylmethyl phosphonium iodide and 0.24 g (8 mmol) of sodium hydride (80% in paraffin oil) in 20 ml of DMSO in an ultrasound bath are brought to reaction at about 55° C. After 10 minutes, 80 mg (0.16 mmol, about 60%) of 3,16α-dihydroxyestra-1,3,5(10)-triene-9 carbaldehyde is added to the solution, and the mixture is allowed to react for 60 more minutes at about 55° C. in an ultrasound bath. After water is added, it is extracted with ethyl acetate. The collected organic phases are washed with water, and the organic phase is concentrated by evaporation in a vacuum.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:25]=1[O:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:38])[NH2:37])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[C:36]([O:35][CH2:34][C@H:31]1[NH:30][CH2:29][C@@H:28]([CH2:27][O:26][C:25]2[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:24]=2[NH:23][C:5](=[O:7])[C@H:4]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[NH:1][C:36]([O:35][CH3:34])=[O:38])[O:33][CH2:32]1)(=[O:38])[NH2:37]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(N)cccc2F)OC[C@H]1COC(N)=O
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN[C@H](COC(N)=O)CO1)[C@@H](c1ccc(F)cc1)c1cccc(F)c1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 5 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=617 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate in dichloromethane (0.13 M) was added triethylamine (1.5 equiv.) followed by methanesulfonyl chloride (1.3 equiv.). The reaction was allowed to stir at room temperature for 15 h. The solution was then quenched with saturated NaHCO3, extracted with dichloromethane, dried with sodium sulfate, and concentrated to give the crude (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)piperidine-1-carboxylate in >95% yield. LCMS (m/z): 428.9/328.9 (MH+), Rt=3.81 min.