Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)=[N:9][C:8]=2[N:7]([CH3:27])[C:6]1=[O:28].Cl.Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[OH:1][CH:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=3)[C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:25])([F:26])[F:24])[CH:17]=3)=[N:9][C:8]=2[N:7]([CH3:27])[C:6]1=[O:28]
Reactant: CC(O)CCn1c(=O)c2[nH]c(Oc3cccc(OC(F)(F)F)c3)nc2n(C)c1=O
Reactant: Cc1ccc(CCl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(Oc3cccc(OC(F)(F)F)c3)nc3c2c(=O)n(CCC(C)O)c(=O)n3C)nc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
To a solution of 1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)— dione (50 mg, 0.121 mmol, intermediate 57) in DMF (3 mL) was added 2-(chloromethyl)-5-methylpyridine hydrochloride (30 mg, 0.182 mmol, intermediate 50), followed by potassium carbonate (50 mg, 0.363 mmol) and TBAI (10 mg, 0.027 mmol). The reaction was stirred at 65° C. overnight. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 1-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (20 mg, 31.9% yield) as white solid. 1H-NMR (CD3OD) δ 8.319(s,1H), 7.663-7.640(d,1H), 7.553-7.510(t,1H), 7.348-7.316(m,3H), 7.233-7.208(m,1H), 5.609(s, 2H), 4.112-4.004(m,2H), 3.763-3.731(m,1H), 3.457(s,3H), 2.339(s,3H), 1.758-1.698(m,2H), 1.197-1.182(d,2H). LCMS retention time 2.714 min; LCMS MH+ 520.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:23]([C:20]1[CH:19]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:21]=1[OH:22])[N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)[CH3:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(Nc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc(CC(=O)O)cc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of a solution of 6.3 g (0.018 mole) of 4-[3,5-di-(tertiary-butyl)-4-hydroxyanilino]phenylacetic acid in 10 ml of N,N-dimethylformamide and 5 g (0.036 mole) of potassium carbonate was heated on a steam bath until gas evolution ceased. The mixture was allowed to cool to ambient temperature, and 5 milliliters of methyl iodide were then added. The mixture was heated at its boiling temperature and 5 ml aliquots of methyl iodide were added at 20, 45 and 60 minutes. After the mixture had evaporated, the residue was taken up in water and 2N sodium hydroxide solution was added. The mixture was warmed, and the insoluble residue of methyl 4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methyl-anilino]phenylacetate was separated by filtration. The residue was suspended and partially dissolved in 50 ml of methanol, and 10 ml of 2.5N sodium hydroxide solution was added. The mixture was stirred for about 16 hours, diluted with 300 ml of water and 300 ml of diethyl ether, and was then further diluted with about 100 ml of hexane. The mixture was acidified with dilute hydrochloric acid and the aqueous phase was discarded. The organic phase was washed first with 10% sodium bicarbonate solution and then with 5% sodium carbonate solution. The product remained in the organic phase as the sodium salt. The organic phase was acidified with 10% aqueous hydrochloric acid and washed with sodium chloride solution, followed by drying. Evaporation provided a residue which was extracted with 20 ml of boiling benzene. Hexane (6 ml) was added, and the light yellow solid was recrystallized first from 80% aqueous ethanol, and then from benzene to provide fine yellow needles of 4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methylanilino]phenylacetic acid, m.p. 181°-182.5° C. Analysis: Calculated for C23H31NO3 ; %C , 74.8; % H, 8.5; % N, 3.8; Found: % C, 74.8; % H, 8.6; % N, 3.6.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([O:13][C:14](C)(C)C)=[O:12])[C:4]=2[CH:3]=1.[Li]CCCC.[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH:9]3[CH:14]([C:31]4[O:32][CH:33]=[CH:29][CH:30]=4)[O:13][C:11](=[O:12])[N:10]3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Product: O=C1OC(c2ccco2)C2c3ccccc3Oc3ccc(Cl)cc3N12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A stirring solution of 1 (2.0 g, 6.04 mmol) in 40 mL of THF was cooled to -78° C. followed by the addition of n-BuLi (1.6M, 4.32 mL, 6.91 mmol). The mixture was stirred at -78° C. for 30 minutes and treated with furalaldehyde (670 mg, 6.97 mmol) and then slowly warmed to room temperature and diluted with 16 mL of water. The mixture was then extracted with ether (200 mL×2) and the combined extracts were washed with brine (saturated, 50 mL) and dried (Na2SO4). The extracts were concentrated to give the crude product (2.5 g), which was purified by HPLC with 20% EtOAc/heptane to yield Compounds 13, 14a and 14b as follows:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)=[CH:4][CH:3]=1.[I-].[N:23]1([C:33](N2C=C[N+](C)=C2)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([O:18][C:33]([N:23]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]2)=[O:34])[CH:11]=3)=[CH:20][CH:21]=1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(4-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.[NH3:12]>CO>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:12])=[N:3][CH:4]=1
Reactant: N
Reactant: O=[N+]([O-])c1cc(F)cnc1Br
Solvent: CO
Product: Nc1ncc(F)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A solution of 2-bromo-5-fluoro-3-nitropyridine (1.176 g, 5.321 mmol) in 2M NH3 in MeOH (20 ml) was sealed in an autoclave and then heated at 75° C. for 6 h and then at 90° C. for a further 18 h. The reaction mixture was then cooled and evaporated, treated with sat. aq. NaHCO3 (100 ml) and then extracted with 5% MeOH/DCM (3×200 ml). The combined organic phases were dried and the solvent was removed. The residue was subjected to column chromatography on silica gel using a 0-5% MeOH in DCM gradient to provide the desired compound as a yellow solid (561 mg, 67%).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[C:7]([Si:10]([CH3:12])([CH3:11])[O:5][CH2:4][C@H:2]1[CH2:1][O:3]1)([CH3:9])([CH3:8])[CH3:6]
Reactant: OC[C@H]1CO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of (S)-glycidol (2.5 g, 33.7 mmol) in 100 mL of 1:1 DCM/DMF was cooled to 0° C. and treated with TBDMS-Cl (6.10 g, 40.5 mmol) and imidazole (3.45 g, 50.6 mmol). The mixture was stirred overnight at 0° C. Solution was diluted with DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated to provide A-1 as a colorless oil. Data for A-1: LRMS m/z (M+H)=189.21 found; 189.34 required
Reaction SMILES: [CH2:1]([C@@H:5]1C[C@@H]([C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CCO[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)OC1=O)[CH:2]=CC.[CH2:44]([NH:48][C:49](=[O:91])[C@H:50]([CH2:87][CH:88]=[CH:89][CH3:90])[CH2:51][C@H:52]([OH:86])[C@@H:53]([NH:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:54][C:55]([CH3:77])([CH3:76])[CH2:56][CH2:57][O:58][Si:59]([C:72]([CH3:75])([CH3:74])[CH3:73])([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:45][CH2:46][CH3:47].C(NC(=O)[C@H](CC(C)=C)C[C@@H]1OC(C)(C=C=O)N(OC(C)(C)C)[C@H]1CC(C)(C)CCOCC1C=CC=CC=1)CCC>>[CH2:44]([NH:48][C:49](=[O:91])[C@H:50]([CH2:87][CH:88]=[CH:89][CH3:90])[CH2:51][C@@H:52]1[O:86][C:1]([CH3:5])([CH3:2])[N:78]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C@H:53]1[CH2:54][C:55]([CH3:76])([CH3:77])[CH2:56][CH2:57][O:58][Si:59]([C:72]([CH3:74])([CH3:73])[CH3:75])([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CC=CC[C@@H]1C[C@@H]([C@H](CC(C)(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC=CC[C@H](C[C@H](O)[C@H](CC(C)(C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Agent: C=C(C)C[C@H](C[C@@H]1OC(C)(C=C=O)N(OC(C)(C)C)[C@H]1CC(C)(C)CCOCc1ccccc1)C(=O)NCCCC
Product: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCCCC

Procedure:
Starting from 472 mg of 3(R)-but-2-enyl-5(S)-[5-tert-butyl-diphenylsilyloxy-1(S)-tert-butoxycarbonylamino-3,3-dimethyl-pentyl]-2-oxo-tetrahydrofuran via 2(R)-but-2-enyl-9-tert-butyldiphenylsilyloxy-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7,7-dimethyl-nonanoic acid (N-butyl)amide (Rf (A)=0.64; FAB-MS: (M+H)+ =681) analogously to Examples 74b and 74c): Rf (B)=0.71; FAB-MS: (M+H)+ =721.
Reaction SMILES: C([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)C1C=CC=CC=1>CO.[Pd]>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C@@H:13]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:21][CH:20]=1
Reactant: COCCOCO[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: COCCOCO[C@@H](CCCCO)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
To a solution of (2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne (2.2 g, 5.4 mmol) in dry methanol (20 ml) was added 10% Pd/C (250mg) and the mixture stirred under H2 at room temperature for 4 h. The reaction mixture was filtered through celite, washed with excess methanol. Evaporation of the solvent afforded a crude product which was purified by silica gel column using ethyl acetate-light petroleum (2:3) as eluent to give (2S)-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hexan-6-ol (1.3 g, 76%) as a colourless liquid. TLC:ethyl acetate-light petroleum (2.3), Rf=0.3. 1H NMR (CDCl3, 200 MHz) δ 1.5-1.7 (m, 6H), 3.35 (s, 3H), 3.5 (t, J=4.8 Hz, 2H), 3.65 (t, J=4.8 Hz, 2H), 3.7-3.8 (m, 2H), 3.85-3.95 (s, 3H), 4.75-4.95 (dd, J=12.6, 6.0 Hz, 2H), 6.75-7.0 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH2:15][CH2:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=1.[C:16]([N:24]=C=O)(=[O:23])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>C(Cl)Cl.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH2:15][CH2:14][N:13]([C:16]([NH2:24])=[O:23])[C:10]3=[N:11][CH:12]=2)[CH:2]=1
Reactant: c1cncc(-c2cnc3c(c2)CCN3)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)N1CCc2cc(-c3cccnc3)cnc21
Temperature: 50 °C
Yield: 63.3 %

Procedure:
5-Pyridin-3-yl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.25 mmol) and benzoyl isocyanate (62 mg, 0.38 mmol) are dissolved in 1.5 mL of DCM. The mixture is heated at 50° C. for 16 hrs. Then the solvent is removed in vacuum and the residue is dissolved in 1.5 mL of EtOH. K2CO3 (60 mg, 0.43 mmol) is added and the mixture is heated at 80° C. for 55 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added DMSO:EtOAc (1:3 mL) mixture and the white solid formed is filtered, rinsed with more EtOAc and dried to give 38 mg of the titled product.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23]2[O:24][C:25]3[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([Br:34])[C:26]=3[CH:27]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Br:34][C:28]1[C:26]2[CH:27]=[C:23]([CH2:22][O:21][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[O:24][C:25]=2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=1
Reactant: COc1ccc(Br)c2cc(COC3CCN(C(=O)OC(C)(C)C)CC3)oc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)c2cc(COC3CCNCC3)oc12
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a stirred solution of 4-(4-bromo-7-methoxybenzofuran-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.3 g) in dichloromethane (50 ml). After stirring at room temperate overnight the reaction was diluted with dichloromethane (150 ml) washed with 1M sodium hydroxide (100 ml) and dried over magnesium sulfate. The organic phase was concentrated in vacuo to afford the title compound as a pale yellow gum (0.98 g).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.N1(C2CCCCCCCCCC2)CCCCCC[CH2:18][CH2:17][CH2:16]N1.BrC(C)C>C1C=CC=CC=1>[CH:17]([N:3]1[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=[C:2]1[Br:1])([CH3:18])[CH3:16]
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: CC(C)Br
Solvent: c1ccccc1
Product: Cc1nc(Br)n(C(C)C)c1C(=O)OC(C)C
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2 g (8.1×10-3 moles) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate in 20 ml of benzene was added 1.2 ml (8.2×10-3 moles) of diazabicycloundecane, followed by 1.0 g. (8.1×10-3 moles) of 2-bromopropane. The resulting mixture was heated to reflux overnight, cooled to room temperature and filtered. Concentration in vacuo gave a golden oil. This residue was purified by medium pressure liquid chromatography on silica gel to yield 1.6 g (70%) isopropyl 1-isopropyl-2-bromo-4-methyl-5-imidazolecarboxylate as a yellow oil, but only 466 milligrams (20%) of the desired product, isopropyl 2-bromo-3-isopropyl-4-methyl-5-imidazolecarboxylate (also a yellow oil), wherein S1 and S3 and R were all CH(CH3)2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:6]2.[CH3:17]N(C=O)C.[H-].[Na+].CI>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[N:6]2[CH3:17]
Reactant: CN(C)C=O
Reactant: Clc1ncnc2nc(-c3ccccc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1c(-c2ccccc2)nc2c(Cl)ncnc21
Reaction time: 0.33 h

Procedure:
To a solution of 6-chloro-8-phenyl-7H-purine (0.200 g, 0.000867 mol) (Example 109, step a) in DMF (8.0 mL, 0.10 mol) was added sodium hydride (0.025 g, 0.0010 mol). The mixture was stirred for 20 minutes and to this was added methyl iodide (0.065 mL, 0.0010 mol) and the mixture was stirred for 2 hours. The reaction was quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (3 to 10% acetone/toluene) to obtain 145 mg (68%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)[CH3:2]>Cl.C(OCC)(=O)C>[NH2:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:17][CH3:18]
Reactant: CCN(CC)CCOCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN(CC)CCOCCN
Yield: 96.1 %

Procedure:
A mixed solution of tert-butyl {2-[2-(diethylamino)ethoxy]ethyl}carbamate (3.77 g) and 4M hydrogen chloride/ethyl acetate solution (40 mL) was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (2.23 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16])=[O:6])[CH3:4].[N:22]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28](O)=[O:29]>CN(C=O)C.CC(O)=O>[N:22]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16])=[O:6])[CH3:4])=[O:29]
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Yield: 54.9 %

Procedure:
After 2.31 g (5.0 mmols) of HCl.H-Ala-Arg(NO2)-CHA was dissolved in 10 ml (15.0 mmols) of 1.5N NEM/DMF, 1.93 g (5.0 mmols) of Z-PyroGlu-SDP was added to the solution at 0° to 5° C. The resulting mixture was reacted at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with 300 ml of AcOH followed by washing 4 times with 100 ml of cold 5% hydrochloric acid and twice with 100 ml of saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate and decoloring with activated charcoal, the AcOEt phase was distilled under reduced pressure. The residue was recrystallized from MeOH/AcOEt/ether to give 18.4 g (54.9%) of Z-pyroGlu-Ala-Arg(NO2)-CHA.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C:32]1[S:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>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.O1CCOCC1>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:35]4[S:36][C:32]([CH2:31][N:27]5[CH2:28][CH2:29][CH2:30][CH:26]5[CH3:25])=[CH:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1CCCN1Cc1ccc(B(O)O)s1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCCC5C)s4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 29.3 %

Procedure:
A solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (36 mg, 0.0862 mmol), {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid (19 mg, 0.0862 mmol) and potassium carbonate (71 mg, 0.517 mmol) was combined in a CEM microwave tube. To this mixture was added water (0.25 mL), dioxane (0.75 mL) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol). The vial was capped and reacted in a CEM microwave for 20 min at 150° C. To this reaction was added tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and reacted in a microwave for 20 min at 150° C. Additional tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) was added, and the reaction was heated in the CEM microwave for an additional 20 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL H2O), eluting in sequence with water (3 mL), MeOH (9 mL), and a 2 M solution of NH3/MeOH (9 mL). The fraction containing crude product solution was concentrated under a stream of nitrogen, and the residue was taken up in DMSO (3 mL). This DMSO solution of crude product was purified as three separate injections (1 mL each) on the Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The two fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 40° C. to give 13 mg of the title compound (29.3%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[NH2:21])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl-].C([O:33][C:34](=O)[C:35](O)=[O:36])C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12]3[C:13](=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[NH:21][C:34](=[O:33])[C:35]2=[O:36])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc([N+](=O)[O-])cc2N)cc1
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-n2c(=O)c(=O)[nH]c3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
At a bath temperature of +4° C., under argon and with exclusion of moisture, 582 mg (2.3 mmol) of 4-(2-amino-4-nitrophenylamino)benzoic acid ethyl ester is combined with 488 mg (4.8 mmol) of triethylamine in 27 ml of dry tetrahydrofuran. A solution of 659 mg (4.8 mmol) of oxalic acid ethyl ester chloride and 8 ml of dry tetrahydrofuran is added dropwise to this batch and stirred for 2 hours at room temperature. The mixture is then combined with 0.2 ml of triethylamine and 0.1 ml of oxalic acid ethyl ester chloride, and agitated for one hour at room temperature. The batch is filtered, and the filtrate is concentrated and distributed in water/ethyl acetate. The organic phase is concentrated. The residue is refluxed for 2 hours at the bath temperature in 25 ml of 1N hydrochloric acid and 25 ml of ethanol. The thus-precipitated product is suctioned off, washed with water, and dried, yielding 220 mg of 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)benzoic acid ethyl ester (further processed without purification).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:21])([F:20])[O:7][C:8]1[CH:19]=[CH:18][C:11]([CH:12](O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:9]=1>>[Cl:3][CH:12]([C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]([F:21])([F:20])[F:5])=[CH:9][CH:10]=1)[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)C(O)c1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)C(Cl)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
To freshly distilled thionyl chloride (14.87 g, 0.125 mol) cooled in salt ice bath is added in portions the neopentyl alcohol of Example 24 (12.4 g, 0.05 mol) over 30 minutes. The ice bath is removed and the slurry is left to stand overnight. Evaporation of excess thionyl chloride gives a solid.