Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]5[CH3:44])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]5[CH3:44])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][O:12][S:55]([CH3:54])(=[O:57])=[O:56])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Example 118 (43 mg, 0.07 mmol) in DCM (1.5 mL) was added DIPEA (49 μL, 0.18 mmol) followed by methanesulfonyl chloride (11 μL, 0.11 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.38 min, m/z 679 [MH+].
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[ClH:32].[CH2:36]([O:35][C:33]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CCOc2c3c(nc4ccccc24)CCN(Cc2ccccc2)CC3)cc1
Product: CCOC(=O)N1CCc2nc3ccccc3c(OCCc3ccccc3)c2CC1
Product: Cl
Yield: 51 %

Procedure:
11-[β-Phenyl-ethyl]oxy-1,2,4,5-tetrahydro-3-azepino[4,5-b] quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 3-benzyl-11-[β-phenyl-ethyl]oxy-1,2,4,5-tetrahydro -3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 208. Yield: 51% of theory; m.p. 153° C.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25](O)([CH3:28])([CH3:27])[CH3:26].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccnc2[nH]ccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 1H-pyrrolo[2,3-b]pyridine-4 carboxylic acid (0.2 g, reference Example 69) in dry dimethylformamide (5 mL), under nitrogen, was treated with 1,1′-carbonyldiimidazole (0.2 g). After stirring at room temperature for 1 hour the resulting tan coloured solution was treated with tert-butanol (260 μL) and DBU (203 μL). This mixture was stirred at 40° C. overnight then evaporated. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL) and the aqueous layer was then extracted twice with ethyl acetate (10 mL). The combined organics were washed twice with brine (10 mL), then dried over sodium sulfate and then evaporated to give the title compound (0.21 g) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:24])[CH2:10][CH:11]=[CH:12][CH2:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCCCCC.CCOCC>C(#N)C>[F:26][CH:11]1[CH2:10][CH:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:24][CH:12]1[CH2:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:15]([CH3:16])[CH3:17])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)[Si](CC=CCC(O)CCc1ccccc1)(C(C)C)C(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)[Si](CC1OC(CCc2ccccc2)CC1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution of 1-phenyl-7-(triisopropylsilyl)hept-5-en-3-ol (149 mg, 0.43 mmol, 1 eq) in acetonitrile (5 mL) was treated with Selectfluor (152 mg, 0.43 mmol, 1 eq) and stirred at room temperature under an atmosphere of argon for 18 h. The acetonitrile was removed under reduced pressure and the reaction was quenched with saturated aqueous sodium hydrogen carbonate (5 mL). It was then extracted with ether (3×10 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to give a pale yellow oil. Column chromatography (hexane:ether, 9:1) gave {[3-fluoro-5-(2-phenylethyl)tetrahydrofuran-2-yl]methyl}(triisopropyl)silane as a colourless oil (157 mg, 66% yield). For the major diastereomer depicted on the left hand side in the pair of formulae above: 1H NMR (400 MHz, CDCl3) δ 0.92-1.00 (dd, 1H, CH2Si, J=14.4, 5.6 Hz), 1.08-1.10 (m, 21H, SiCHCH3), 1.19-1.26 (m, 1H, CH2Si) 1.66-1.89 (m, 2H, PhCH2CH2), 1.93-2.02 (m, 1H, CH2CHF), 2.26-2.43 (m, 1H, CH2CHF), 2.60-2.83 (m, 2H, PhCH2), 3.70-3.81 (m, 1H, PhCH2CH2CHO), 4.06-4.17 (dddd, 1H, OCHCHF, J=27.6, 8.4, 5.6, 2.8 Hz), 4.83-4.98 (m, 1H, CHF); 13C NMR (100 MHz, CDCl3) δ 8.21-8.26 (CH2Si), 11.4 (Si(CH(CH3)2)3), 18.9 (Si(CH(CH3)2)3), 32.5 (PhCH2), 38.0 (PhCH2CH2), 39.2-39.4 (d, CH2CHF, J=21 Hz), 76.1 (PhCH2CH2CHO), 78.6-78.8 (d, CHFCHO, J=20 Hz), 94.6-96.5 (d, CHF, J=182), 125.7 (Ph), 125.8 (Ph), 128.3 (Ph), 128.4 (Ph), 142.1 (Ph); 19F NMR (376.5 MHz, CDCl3) δ −191.5 For the major diastereomer depicted on the right hand side in the pair of formulae above: 1H NMR (400 MHz, CDCl3) δ 0.92-1.00 (dd, 1H, CH2Si, J=14.4, 5.6 Hz), 1.08-1.10 (m, 21H, SiCHCH3 ), 1.19-1.26 (m, 1H, CH2Si) 1.66-1.89 (m, 2H, PhCH2CH2), 1.93-2.02 (m, 1H, CH2CHF), 2.26-2.43 (m, 1H, CH2CHF), 2.60-2.83 (m, 2H, PhCH2), 3.70-3.81 (m, 1H, PhCH2CH2CHO), 4.20-4.27 (m, 1H, OCHCHF), 4.78-4.93 (m, 1H, CHF); 13C NMR (100 MHz, CDCl3) δ 8.75-8.82 (CH2Si), 11.4 (Si(CH(CH3)2)3), 18.9 (Si(CH(CH3)2)3), 32.7 (PhCH2), 38.2 (PhCH2CH2), 39.6-39.9 (d, CH2CHF, J=21 Hz), 77.2 (PhCH2CH2CHO), 80.1-80.3 (d, CHFCHO, J=21 Hz), 94.0-94.5 (d, CHF, J=183), 125.8 (Ph), 128.3 (Ph), 128.4 (Ph), 128.5 (Ph), 142.1 (Ph); 19F NMR (376.5 MHz, CDCl3) δ −185.5; IR (v, cm−1) 3027 (Ar—H), 1496 (Ar), 1464 (Ar), 1384 (Ar), 1096 (C—O—C), 699 (Si—C); MS (GCT, CI+) m/z 226.2 [M+NH4]+ HRMS required for C22H41FNOSi: 382.2941, found 382.2935.
Reaction SMILES: Cl[C:2]1[C:3](=[O:22])[C:4]2[CH:21]=CC=C[C:5]=2[C:6]2[C:15]=1OC1C(=CC(CBr)=CC=1)N=2.[O:23]=[CH:24][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[BH:35]([O-:45])[O:36]C1C=CC=CC=1NC>>[C:4]1([CH3:21])[CH:5]=[CH:6][CH:15]=[CH:2][C:3]=1[B:35]([OH:45])[OH:36].[OH:23][CH2:24][C:4]([CH3:5])([CH2:3][OH:22])[CH3:21]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CNc1ccccc1OB[O-]
Reactant: O=c1c(Cl)c2oc3ccc(CBr)cc3nc-2c2ccccc12
Product: CC(C)(CO)CO
Product: Cc1ccccc1B(O)O

Procedure:
Nevertheless, benzophenoxazinone bromide 6a had been prepared and now required attachment with the glucose binding boronate unit. The preparation of the benzophenoxazinone coupling partner, aminophenyl boronate 10, required protection of o-tolylboronic acid 7 with neopentyl glycol to give the corresponding o-tolylboronic ester 8 in 99% yield. Boronic ester 8 was functionalized by free radical bromination using N-bromosuccinimide in carbon tetrachloride and AIBN as the initiator. The reaction conditions required heating, as well as, irradiation with a light source to give bromomethylphenyl boronate 9 in 97% yield. Subsequently, amino boronate derivative 10 was synthesized by bubbling methylamine through a etheral solution of phenyl boronate 9. Methylaminophenyl boronate 10 was isolated cleanly in 99% yield (FIG. 23).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O:21][C:22](=O)[C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C>C(O)C>[OH:30][C:23]1[C:22](=[O:21])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:15]([C:14]2[CH:17]=[CH:18][C:11]([OH:10])=[CH:12][CH:13]=2)[C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCC(=O)C(=O)OCC
Reactant: NCCCn1ccnc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Product: CCCCCC1=C(O)C(=O)N(CCCn2ccnc2)C1c1ccc(O)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 4-Hydroxy-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-octanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=5)[CH:31]=4)[CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:56]OC(=O)NC(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(Br)C=3)C=2)=CN=1)=O)C(C)C.C(OC(N1C(C2NC(C3C=CC(B4OC(C)(C)C(C)(C)O4)=CC=3)=CN=2)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:14]2[NH:15][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:35]6[NH:36][C:37]([CH:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:48])[CH3:49])=[N:38][CH:39]=6)[CH:31]=5)[CH:26]=4)=[CH:23][CH:24]=3)=[CH:17][N:18]=2)[CH:10]2[CH2:56][CH:12]1[CH2:13][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 46 %

Procedure:
This compound was synthesized using the procedure used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.161 g, 0.322 mmol) and 3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.195 g, 0.419 mmol) to give 3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.133 g, 46% yield). LCMS-ESI+: calc'd for C44H51N7O5: 757.40 (M+); Found: 758.26 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.C(OCC)(=O)C>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (75 g, 241.86 mmol, 1.0 eq), triethylamine (75 mL, 538.08 mmol, 2.22 eq), and 10% palladium on activated carbon (8.2 g) in ethanol (1350 mL) is stirred under hydrogen flow at room temperature for 6 hours. The catalyst is then removed by filtration and the solution is evaporated to dryness to give a yellow solid as crude product, which is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a light yellow powder (46.2 g, 77% yield).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl-].Cl[CH2:23][CH2:24][NH+:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:31]=[S:28]1(=[O:32])[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=4)[CH:8]=3)[CH2:2][CH2:3]2)[CH2:26][CH2:27]1
Reactant: O=S1(=O)CC[NH+](CCCl)CC1
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(Nc2cc(N3CCN(CCN4CCS(=O)(=O)CC4)CC3)ncn2)s1
Temperature: 200 °C

Procedure:
12-3 (0.20 g, 0.39 mmol), 41-2 (0.11 g, 0.47 mmol) and DIEA (0.30 g, 2.33 mmol) were suspended in DMF (1 mL) in a sealed tube and heated at 200° C. for 15 minutes in the Smith personal chemistry microwave reactor. The crude material was purified on a C18 preparative hplc column to afford 41-3. Hi-Res MS: calc: 449.1576 found: 449.1532. 1H-NMR(CD3OD): 8.49(s, 1H); 8.02(s, 1H); 6.28(s, 1H); 4.02(m, 4H); 3.48(br s, 4H); 3.39(t, 2H); 3.16(m, 4H); 3.12(m, 4H); 2.97(m, 2H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([C:19]#N)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O:23]CC)C>>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:19](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOCC
Reactant: CCCCCCCCC#N
Reactant: CCCCCCCC[Mg]Br
Product: CCCCCCCCC(=O)CCCCCCCC
Reaction time: 12 h
Yield: 71 %

Procedure:
A Grignard solution of n-octylmagnesiumbromide in diethylether (2.0 M, 100 mL, 0.2 mol) was slowly added via syringe to a stirred mixture of n-octylcyanide (13.92 g, 0.1 mol) in diethyl ether (100 mL) at 0° C. under N2 atmosphere. After stirring for 12 h at reflux temperature, the reaction was quenched with an aqueous HCl-solution (2.0 M, 50 mL) at 0° C. and subsequently vigorously stirred for an additional 3 h at room temperature. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with a saturated bicarbonate solution and brine, dried over MgSO4 and evaporated under reduced pressure to give an orange solid. The resulting solid was purified recrystallization from methanol to afford yellow crystals (VIII) (18.06 g, 71%). 1H-NMR (CDCl3): δ=2.33 (t, J=7.4 Hz, 4H), 1.58-1.44 (m, 4H), 1.30-1.10 (s, 20H), 0.82 (t, J=6.4 Hz, 6H). 13C-NMR (CDCl3): δ=212.33, 43.42, 32.44, 30.01, 29.90, 29.78, 24.49, 23.26, 14.70.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[CH2:28][CH3:29])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:32](O)(=[O:34])[CH3:33].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:32]([NH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:27])([C:19]([F:20])([F:21])[F:22])[C:23]([F:24])([F:25])[F:26])=[CH:13][C:12]=2[CH2:28][CH3:29])=[O:9])=[CH:30][CH:31]=1)[CH3:3])(=[O:34])[CH3:33]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)N)cc1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
4-(1-Aminoethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]benz amide (0.4 g) was dissolved in methylene chloride (15 ml). To the solution, acetic acid (0.06 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g) and an catalytic amount of dimethylaminopyridine were added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and the residue was added with water followed by extraction twice with ethyl acetate. The organic phases were combined, washed with water and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 4-(1-acetamidoethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro propan-2-yl)-6-methylphenyl]benzamide (0.35 g, yield 95%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].[CH3:10][O:11][C:12]([C:14]1[C:15]([CH2:20]Cl)=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13]>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[C:15]([CH2:20][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: COC(=O)c1cccnc1CCl
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1Cn1cccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (5.8 g, 0.12 mol), in dry N,N-dimethyl formamide (25 mL) was added slowly under nitrogen a solution of pyrrole 2-carboxaldehyde (10.5 g, 0.11 mol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then cooled to 5° C. and 2-chloromethyl-pyridine-3-carboxylic acid methyl ester of Step A was added slowly, the temperature being maintained at or below 20° C. After the addition was complete, the reaction was stirred at room temperature for 30 minutes. The mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate (250 mL). This solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed in vacuo leaving a dark crystalline solid (23.4 g), which was purified by chromatography on silica gel eluting with a gradient of ethyl acetate/petroleum ether to provide the title compound as a tan crystalline solid (13.75 g), m.p. 91–93° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>O.C1COCC1>[NH:14]([C:9]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=1)=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-Methoxycarbonyl benzoic acid (540 mg), aniline (0.27 ml), WSC (863 mg) and triethylamine (0.84 ml) were added to THF (20 ml). After the reaction mixture was stirred at room temperature for 20 hours, the reaction mixture was placed in water, and extraction was conducted using ethyl acetate-THF (1:1). The organic layer was washed with water, saturated sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to give the titled compound (659 mg).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[N+:2]=[N-:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNS(=O)(=O)c1ccccc1
Yield: 84 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, benzenesulfonyl chloride (0.201 g, 1.16 mmol) was reacted with 2-azidoethanamine (0.100 g, 1.16 mmol) and triethylamine (0.235 g, 2.32 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)benzenesulfonamide (0.289 g, 84%). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, 2H), δ 7.55 (m, 3H), δ 5.47 (s, 1H), δ 3.39 (t, 2H), δ 3.12 (t, 211) ppm; 13C NMR (75 MHz, CDCl3) δ 139.8, 133.2, 129.5, 127.2, 50.9, 42.6 ppm; HRMS (ESI) calcd for C6H8N4O2S (M+) 226.0524. Found 226.0523.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([NH2:17])=[CH:12][N:11]=1>CO>[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[N:17]=[C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])[S:8][C:14]=2[N:15]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)N=C=S
Solvent: CO
Product: CCOC(=O)Nc1nc2cnc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
Ethoxycarbonyl isothiocyanate (4.32 mL, 36.6 mmol) and 2,4-dichloro-pyrimidin-5-ylamine (3.00 g, 18.29 mmol) were mixed neat and sonicated for 5 minutes to help dissolve. The mixture was stirred at ambient temperature for 10 minutes, at which time the entire mixture had solidified. Methanol (100 mL) was added and the mixture was refluxed for 30 minutes, cooled to ambient temperature and the solids were collected by filtration to afford ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (3.8 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.64 (s, 1 H) 9.05 (s, 1 H) 4.31 (q, J=7.19 Hz, 2 H) 1.32 (t, J=7.15 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C2C(COC([N:32]=[C:33]=[S:34])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:33](=[S:34])[NH2:32])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CC1CCNCC1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CC1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of piperidin-4-ylacetic acid tert-butyl ester (10.72 g, 50.0 mmol) in chloroform (100 ml) was added to a solution of 9-fluorenylmethoxycarbonyl isothiocyanate (14.07 g, 50.0 mmol) in chloroform (100 ml) and the mixture was stirred at room temperature for 1 hour. Then, piperidine (80 ml) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, water was added, and it was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over magnesium sulfate and the residue obtained by vacuum concentration was washed with isopropyl ether and the title compound was obtained (11.35 g, 98%).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:41](=[O:43])[CH3:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[N:32]=[C:31]2[C:30](=[CH:29][CH:28]=1)[N:33]=[CH:34][C:35]([C:41](=[O:43])[CH3:42])=[C:36]2[OH:38]
Reactant: CCOC(=O)C(=CNc1ccc(Cl)nc1)C(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1O
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To a flask containing Dowtherm™ A (500 mL) at 250° C. was added ethyl 2-[(6-chloropyridin-3-ylamino)methylene]-3-oxobutanoate (10 g, 27 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and dried under vacuum to afford the intermediate 1-(6-chloro-4-hydroxy-1,5-naphthyridin-3-yl)ethanone which was heated in neat phosphorus oxychloride with catalytic N,N-dimethylformamide for 4 h at 70° C. The reaction was cooled and poured slowly into a vigorously stirring mixture of ice-cold satd. aq. sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to provide the desired product (3 g, 46% over two steps) as a brown solid: ESI MS m/z 241 [M+H]+.