Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH3:16])[CH2:14][NH:15][C:29](=[O:30])[C:28]3[CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=[N:26][CH:27]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 28 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (75 mg, yield 28%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.47-9.46 (d, J=2.0 Hz, 1H), 9.33 (d, J=2.0 Hz, 1H), 8.88-8.87 (t, J=2.1 Hz, 1H), 8.11-8.04 (m, 3H), 7.54 (d, J=1.0 Hz, 1H), 7.18-7.14 (t, J=8.8 Hz, 2H), 4.02-3.96 (ddd, J=13.2 Hz, 6.5 Hz, 4.1 Hz, 1H), 3.53-3.46 (ddd, J=13.1 Hz, 9.0 Hz, 4.3 Hz, 1H), 3.20-3.11 (m, 1H), 1.42-1.40 (d, J=7.0 Hz, 3H). MS (ESI) m/z: Calculated for C21H15F4N5O3: 461.11. found: 462.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C[O-].[Na+].OC1C=CC(NC(=O)N(C)C)=CC=1.[Na].[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>CS(C)=O.CO>[Cl:31][C:32]1[N:37]=[C:36]([O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[N:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=2)[CH:35]=[CH:34][N:33]=1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CN(C)C(=O)Nc1ccc(Oc2ccnc(Cl)n2)cc1

Procedure:
4-Hydroxyphenyl-N,N-dimethylurea (12.0 grams; 0.066 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (1.53 grams) in 55 milliliters (ml) of methanol) and the resulting sodium 4-hydroxyphenyl-N,N-dimethylurea solution added gradually over a period of about one hour to a solution of 2,4-dichloropyrimidine (9.94 grams; 0.066 mole) in 50 ml. of dimethylsulfoxide. During the addition, the reaction temperature rose from about 55°C. to a temperature from between about 60° to about 65°C. The resulting reaction mixture was maintained at temperatures from between about 60° to about 70°C. for a period of about 30 minutes. The reaction mixture, which was nearly neutral, was poured into about 300 ml. of cold water and the resulting product precipitate recovered by filtration and washed with additional portions of water. The product precipitate was dissolved in acetonitrile and the resulting solution filtered with activated charcoal and then cooled to crystallize the product. The product thus obtained was recrystallized again from methylene chloride and dried. As a result of these operations, the desired title product was obtained as a white solid having a melting point of 192°C.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][CH:5]=1.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[CH2:16][C:17]#[N:18].O>C(O)(C)(C)C>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[CH:16]([C:3]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:12])[C:17]#[N:18]
Reactant: COC(=O)c1ccc(OC)nc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)C(C#N)c2ccc(Cl)cc2Cl)cn1
Temperature: 100 °C
Yield: 29.3 %

Procedure:
To a suspension of potassium-tert-butylate (2.052 g) in tert-butanol (25 ml) was added methyl-6-methoxynicotinate (2.5 g). 2,4-Dichlorobenzyl cyanide (2.782 g) was added potion wise. The mixture was heated to 100° C. for 1.5 h. After cooling to room temperature, water (100 ml) was added and the mixture was washed with diethyl ether. The aqueous phase was neutralized with concentrated aqueous HCl and extracted with EtOAc. The organic phase was washed with water and with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound (1.407 g) as a yellow foam that was used in the next step without further purification. MS (m/e)=321.0 [M+H+].
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:15][CH:12]2[CH2:14][CH2:13]2)[N:5]=1)([CH3:11])[CH3:10]
Reactant: NC1CC1
Reactant: CC(C)c1nc(CCl)cs1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(CNC2CC2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of 1.8 g (10.2 mmol) of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 10 ml of chloroform was added dropwise with stirring to 10 ml of cyclopropylamine. The resulting solution was stirred at ambient temperature for 16 h, concentrated in vacuo, and purified by silica gel chromatography using 5% methanol in chloroform to provide 0.39 g (19%) of the desired compound. 1H NMR (DMSO-d6) δ 0.24 (m, 2 H), 0.35 (m, 2H),1.30 (d, J=7 Hz, 6 H), 2.10 (tt, J=12, 3 Hz, 1 H), 3.23 (heptet, J=7 Hz, 1 H), 3.77 (s, 2 H), 7.21 (s, 1 H). Mass spectrum: (M+H)+ =197.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: COc1ccc(-c2nc3cc(OC)cc(-c4nccs4)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 53, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole and 2-(tributylstannyl)thiazole. The product was obtained as an off white solid (93% yield, m.p. 132-136° C.); MS m/e 339 (M+H)+.
Reaction SMILES: N.[Na].[N:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:15][CH3:16])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C1[O:19]C1.[Cl-].[NH4+]>C(OCC)C>[N:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH2:15][CH2:16][OH:19])=[CH:5][CH:4]=1
Reactant: C1CO1
Reactant: CCC(CCN(C)C)c1ccncc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)CCC(CCO)c1ccncc1
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To stirred liquid ammonia (2 liters) was added ferric nitrate (0.1 gm) followed by sodium metal (8.0 gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution was added 3-(4-pyridyl)-1-dimethylaminopentane (49 gms) over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Liquid ethylene oxide (14.6 gms) was then added and the mixture was stirred for a further 3 hours. Solid ammonium chloride (20 gms) was then added in small portions, followed by diethyl ether (1 liter). The ammonia was allowed to evaporate overnight and the residual mixture was filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to yield 3-(4-pyridyl)-5-dimethylamino pentan-1-ol (32 gms, 46% conversion) b.p. 140°-146° C/0.5 mm Hg (m.p. 26° C).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]([C:32](=[O:56])[NH:33][CH2:34][C:35](=[O:55])[NH:36][CH2:37][C@@H:38]([C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH:39]C(=O)OCC2C=CC=CC=2)[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.NC[C@H](N[S:67]([CH2:70][C:71]12[C:77]([CH3:79])([CH3:78])[CH:74]([CH2:75][CH2:76]1)[CH2:73][C:72]2=[O:80])(=[O:69])=[O:68])C(OCC)=O.C(OC(N1CCC(CCC(CCC2CCN(C(OC(C)(C)C)=O)CC2)C(NCC(O)=O)=O)CC1)=O)(C)(C)C>>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][CH:16]([C:32](=[O:56])[NH:33][CH2:34][C:35](=[O:55])[NH:36][CH2:37][C@@H:38]([C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH:39][S:67](=[O:68])(=[O:69])[CH2:70][C:71]23[C:77]([CH3:79])([CH3:78])[CH:74]([CH2:75][CH2:76]2)[CH2:73][C:72]3=[O:80])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@H](CN)NS(=O)(=O)CC12CCC(CC1=O)C2(C)C
Agent: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Agent: Cl
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NS(=O)(=O)CC12CCC(CC1=O)C2(C)C

Procedure:
According to the procedure described for compound 29, starting with ethyl (2S)-3-amino-2-({[(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methyl]sulphonyl}amino)propanoate hydrochloride and compound 4.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[N:3]=1.[O:16]1CCOCC1>O>[CH:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[N:3]=1)=[O:16]
Reactant: COC(=O)c1ccc2ccc(C)nc2c1
Reactant: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2ccc(C=O)nc2c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of methyl 2-methylquinoline-7-carboxylate (0.99 g, 4.92 mmol) in dioxane (60 mL) and water (0.6 mL) was added SeO2 (0.66 g, 5.90 mmol) and the mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:4 hexane/ethyl acetate) to give methyl 2-formylquinoline-7-carboxylate (0.75 g, 70.8%) as a solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:23])=[CH:25][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCc1ccc(C(=O)O)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCc1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.264 g (1.2 mol) of 4-heptylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH2:19][CH2:20][N:21]4[CH2:26][C:27]3([NH:35]C(=O)OC(C)(C)C)[CH2:32][O:31]C(C)(C)[O:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:35][C:27]([CH2:26][N:21]1[C:22]2[C:18](=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH3:11])=[C:2]([I:1])[CH:3]=4)[O:16][N:15]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:19][CH2:20]1)([CH2:28][OH:29])[CH2:32][OH:31]
Reactant: CCCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1I
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCCOc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cc1I
Yield: 75 %

Procedure:
When the product of Step F was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 75% yield., as a colourless solid. 1H-NMR (DMSO-d6) 1.02 (tr, 3H, J=7.3 Hz); 1.4 (broad s, 2H); 1.72-1.8 (m, 2H); 2.98 (s, 2H); 3.2-3.4 (m, 6H+H2O); 3.53 (tr, 2H, J=8.3 Hz); 4.09 3.53 (tr, 2H, J=6.1 Hz); 4.56 (broad s, 2H); 6.76 (d, 1H, J=7.7 Hz); 7.09-7.25 (m, 3H); 8.1 (d, 1H, J=8.8 Hz); 8.44 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[C:18]3[C:13]([N:14]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:15](=[O:27])[NH:16][C:17]3=[O:26])=[N:12]2)=[CH:2]1.N12C[CH2:41][CH2:40][N:39]=[C:38]1[CH2:37][CH2:36][CH2:35]CC2.Cl.ClCC1C=CN=CC=1>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[C:18]3[C:13]([N:14]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:15](=[O:27])[N:16]([CH2:41][C:40]4[CH:35]=[CH:36][CH:37]=[CH:38][N:39]=4)[C:17]3=[O:26])=[N:12]2)=[CH:2]1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Agent: ClCc1ccncc1
Solvent: CS(C)=O
Product: CC(C)Cn1c(=O)n(Cc2ccccn2)c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Temperature: 80 °C

Procedure:
2-(1-benzothien-3-ylmethyl)-7-isobutyl-3-(1-methyl-1H-pyrrol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was dissolved in anhydrous dimethylsulfoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene was added. 4-chloromethylpyridine hydrochloride was added and the mixture was heated at 80° C. for 18 h. The crude reaction product was purified by semi-prep RPHPLC eluting with water/acetonitrlle/trifluoroacetic acid mixtures. 525 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:37][CH2:36][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:29][C:25]=2[CH3:24])=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CCNC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a solution of 3-[2-(2-tert-butoxycarbonylamino-ethyl)-4-hydroxy-phenyl]-propionic acid methyl ester (0.807 g, 2.50 mmol) and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (1.34 g, 3.74 mmol) in DMF (5 mL) was added Cs2CO3 (1.22 g, 3.74 mmol). The suspension was stirred at 65° C. for 48 h, quenched with H2O (200 mL), and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4) and concentrated to a residue, which was purified on silica gel chromatography (hexanes/EtOAc 9/1 to 8/2 to 6/4) to afford the title compound as a colorless oil (0.90 g, 71%). 1H NMR (400 MHz, CDCl3): δ 1.42 (s, 9H), 2.37 (s, 3H), 2.54 (t, 2H, J=7.8 Hz), 2.77 (t, 2H, J=7.8 Hz), 2.88 (t, 2H, J=6.8 Hz), 2.96 (t, 2H, J=6.8 Hz), 3.33 (˜dt, 2H, J=6.8 Hz), 3.65 (s, 3H), 4.20 (t, 2H, J=6.8 Hz), 6.70 (br s, 1H), 6.72 (d, 1H, J=8.3 Hz), 7.05 (d, 1H, J=8.3 Hz), 7.39-7.44 (m, 3H), 7.95-7.98 (m, 2H). MS (ES+) m/z [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[NH2:14][C:15]([CH3:36])([CH3:35])[CH2:16][N:17]1[C:29]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34]>ClCCl>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][O:32][CH2:33][CH3:34])[N:17]([CH2:16][C:15]([NH:14][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])([CH3:35])[CH3:36])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)N
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)C(C)C
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Triethylamine (556 μL, 4.00 mmol) and isobutyryl chloride (230 μL, 2.20 mmol) were added sequentially to a chilled (0° C.) solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (628 mg, 2.00 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted with dichloromethane (50 mL). The organic layer was separated, washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to an amber foam. This material was dissolved in hot propyl acetate (10 mL) and then allowed to cool overnight. Hexanes were added and the now cloudy solution was heated until clear and then allowed stand until crystals formed. The solvent was removed by pipette. The crystals were rinsed with cold propyl acetate/hexanes and then dried under high vacuum at 70° C. to provide 464 mg of N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]-2-methylpropionamide as an off white crystalline solid, mp 154.5-155.5° C. Anal. calcd for C20H28N6O2: % C, 62.48; % H, 7.34; % N, 21.86. Found: % C, 62.14; % H, 7.62; % N, 21.71.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[C:20](O)=[O:21])=[O:6])[CH:2]=[CH2:3].[CH:23]1(N=C=NC2CCCCC2)CCCCC1.CC1(C)OC(=O)CC(=O)O1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:20]([C@@H:8]1[CH2:9][C@@H:10]([O:12][Si:13]([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14])[CH2:11][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:21])[CH3:23]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-carboxypyrrolidine (15 g) in dichloromethane (150 ml) were added dicyclohexylcarbodiimide (11.5 g), Meldrum's acid (8.0 g) and 4-dimethylaminopyridine (6.8 g) at 0° C. After stirring for 24 hours at ambient temperature, the resulting precipitate was removed by filtration. The filtrate was washed with 1N hydrochloric acid solution, and evaporated in vacuo. The residue was dissolved in a mixture of acetic acid (80 ml) and water (60 ml), and refluxed for 1 hour. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The solution was washed in turn with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in dimethylformamide (60 ml) and then imidazole (8.7 g) and t-butyldimethylsilyl chloride (8.7 g) were added thereto at ambient temperature. After stirring for 10 hour, the mixture was poured into water (200 ml), extracted with ethyl acetate (100 ml×2), dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give (2S,4R)-2-acetyl-1-allyloxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine (10.6 g).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([O:41]C)=[O:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.[OH-].[Na+].CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1>CC(C)=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)OC
Agent: Cc1cc(O)c(C(C)C)cc1C1(c2cc(C(C)C)c(O)cc2C)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
1.15 g. (1.6 mmoles) of Z-Tyr-D-Ala-Gly-Phe-Nle-OMe (3rd step of Example 1) are suspended in a mixture of 4 ml. of methanol and 2 ml. of acetone, then saponified with 0.5N sodium hydroxide in the presence of thymolphthalein as indicator. When the alkali consumption becomes slower, the mixture is diluted with 10 ml. of water and shaken with 3×5 ml. of ethyl acetate. On evaporating the ethyl acetate phases 0.3 g. (26%) of protected pentapeptide ester is recovered. The aqueous phase is acidified with 0.5N sulphuric acid, the precipitated substance (Rf2 0.25-0.35) suspended in 50 ml. of 80% acetic acid and hydrogenated in the presence of palladium catalyst. In the course of the reaction the substance is dissolved. At the end of the reaction the catalyst is filtered off, the solution evaporated and the residue rubbed with about 4 ml. of cold water. The formed crystalline substance is filtered, washed with cold water and dried. Yield: 0.47 g. (70%) of the named product; Rf4 0.19-0.23. Aminoacid analysis: Gly=1.0, Ala=1.02; Nle=1.02; Tyr=0.98; Phe=1 (reference basis).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16]([OH:18])=[S:17])=[CH:5][CH:4]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16]([O:18][CH3:19])=[S:17])=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cc2cnccc2C(O)=S)cc1
Solvent: CN(C)C=O
Product: COC(=S)c1ccncc1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.8 %

Procedure:
A solution of 4.9 g (17.8 mmol) of 3-(4-methoxyphenyl)methylthiopyridine-4-carboxylic acid and 4.9 g (30 mmol) of carbonyldiimidazole in 50 mL of dry N,N-dimethylformamide was stirred at 0° C. for 10 minutes and then allowed to warm to room temperature. After 2 hours the solution was cooled to 10° C. and quenched with 20 mL of methanol. The mixture was stirred for 2 hours and then the solvent was concentrated. The residue was partitioned between ether and water and the aqueous layer was extracted with three portions of ether. The ether extracts were dried (MgSO4) and concentrated to afford 5.1 g (93%) of a crystalline solid, m.p. 99°-100° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=1.COCCOC.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C(O)C>[CH3:12][S:9]([CH2:8][C:6]1[CH:5]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=[C:2]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[N:7]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1
Yield: 26.9 %

Procedure:
2-Chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine (5 g, 17.1 mmol), was dissolved in a mixture of DMF:DME:water:ethanol (16.5 mL:41 mL:18 mL:12 mL). 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.62 g, 25.6 mmol), a 2M aqueous solution of sodium carbonate (25 mL), and dichlorobis(triphenylphosphine) palladium (600 mg) were added and the mixture refluxed for 5 hours under a nitrogen atmosphere. The mixture was cooled, diluted with water and extracted into DCM. The organic layer was dried over Na2SO4, filtered and evaporated. The crude material was dissolved in minimum of hot DCM then hexane added and the precipitate filtered to give the desired material (1.6 g).