Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([Li:18])=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)oc1ccccc12
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a solution of dibenzo[b,d]furan (4.98 g, 29.6 mmol) in ether (50 mL) at −78° C. was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise and the solution was allowed to warm to room temperature and stirred for 20 h to yield a dibenzo[b,d]furan-4-yl lithium solution. Into a solution of 1,3-dibromobenzene (2.56 mL, 21.20 mmol) in ether (50 mL) was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise at −78° C. The reaction solution was stirred at this temperature for 3.5 h before adding into a solution of dichlorodiphenylsilane (4.88 mL, 23.70 mmol) in ether (50.0 mL) at −78° C. The resultant reaction solution was stirred at this temperature for 2 h before the dibenzo[b,d]furan-4-yl lithium solution prepared above was introduced dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight at which time it was quenched with water, extracted with ether, and dried over Na2SO4. Upon filtration and evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (9/1, v/v) as eluent to yield (3-bromophenyl)(dibenzo[b,d]furan-4-yl)diphenylsilane (6.2 g, 52%) as a white powder.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.Cl.[NH2:13][OH:14].O>CO>[OH:14][N:13]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: NO
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CO
Solvent: O
Product: ON=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Piperonal(15.0 g, 0.10 mol) was dissolved in methanol(150 ml), and hydroxylamine hydrochloride(10.5 g, 0.15 mol) and water(15 ml) were added thereto. The mixture was stirred for 1 hour at room temperature, then excess water was added, and the resulting mixture was stirred for further 1 hour. The white solid thus obtained was washed with water under reduced pressure, filtered, and dried to give (hydroxyimino)-(benzo[3,4-d]1,3-dioxolan-5-yl)methane(15.7 g, Yield 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:16])[C:14]2[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cc(C(F)(F)F)ccc1F
Reaction time: 16 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.4 g, 2.32 mmol) was diluted with THF (12 mL), treated with 2-fluoro-5-trifluoromethyl-benzoyl chloride (0.388 g, 2.56 mmol) and stirred for 16 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (0.5 g, 60%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].C[O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])=[O:26].Cl>>[C:17]1([S:14]([N:6]2[C:7]3[C:12](=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:4]([C:1](=[O:3])[CH:2]=[C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:25]([OH:26])=[O:24])[CH:28]=3)[OH:31])=[CH:5]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Agent: Cl
Product: O=C(O)c1cccc(C(O)=CC(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(Cl)cc23)c1

Procedure:
In accordance with Example 99, 3-acetyl-1-benzenesulfonyl-5-chloroindole reacted with 3-methoxycarbonyl benzoylchloride, followed by hydrolysis with hydrochloric acid to give the titled compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[F:10][C:9]([F:12])([F:11])[C:8]([C:6]1[N:7]=[C:2]([CH:26]=[O:27])[CH:3]=[CH:4][CH:5]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: OC(c1cccc(Br)n1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)n1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 261 (0.5 g, 1.54 mmol) in dry THF, cooled to 0° C., n-BuLi (0.118 g, 1.85 mmol) was added drop wise and continued stirring for 10 min. Then DMF (0.224 g, 3.08 mmol) was added to the reaction mixture while stirring for another 2 h. After completion of the reaction, it was quenched with saturated ammonium chloride solution. The organic layer was separated and aqueous phase was extracted again with diethyl ether, the combined organic layer was dried over sodium sulphate and concentrated to get the crude compound 6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)picolinaldehyde 262.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[N:32]O)[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C1(C)C(S(Cl)(=O)=[O:41])=CC=CC=1>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@H:24]3[C@H:25]4[O:31][CH2:30][C:29](=[O:41])[NH:32][C@H:26]4[O:27][CH2:28]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: ON=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Solvent: CO
Solvent: c1ccncc1
Product: O=C1CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R,3aS,6aR)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one oxime (20 mg, 0.043 mmol) was dissolved in pyridine and was cooled in an ice bath. Toluene sulfonyl chloride (21.2 mg, 0.11 mmol) was added in one portion and the mixture was stirred in an ice bath for 1 hour. The mixture was warmed to room temperature and additional toluene sulfonyl chloride (17 mg, 0.09 mmol) was added. After 2 hours, the solution was placed in a 60 degree oil bath for 1.5 hours and then cooled to room temperature. The reaction mixture was evaporated to give a foam, which was dissolved in methanol (2 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water to give the title compound. LC-MS: calculated for C24H19ClN4O4 462.11 observed m/e: 463.95 (M+14)+ (Rt 1.25/2 min); 1H NMR δ (ppm) (CD3OD): 7.93 (s, 1H), 7.78 and 7.73 (ABq, 4H), 7.70 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 6.44 (d, 1H), 5.48 (t, 1H), 4.83 (t, 1H), 4.63 (ABq, 2H), 4.50 (dd, 2H) and 4.45 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Li]CCCC.Cl[P:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:25]1([P:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Brc1cccc2cccnc12
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a stirred solution of 8-bromoquinoline (20.8 g, 100 mmol) in dry THF (200 mL) under nitrogen was added n-BuLi (62.5 mL, 1.6 M in hexanes, 100 mmol) at −78° C. and the mixture was stirred for 30 minutes. Chlorodiphenylphosphine (17.9 mL, 100 mmol) was then added and the solution was allowed to warm up to room temperature and stirred for 2 h. The solution was then cooled to −78° C. and quenched by addition of saturated aqueous NH4Cl solution (100 mL). After warming up to room temperature, the solution was filtered, the precipitated solid collected, taken up in CH2Cl2 (200 mL) and filtered over silica gel eluting with further portions of CH2Cl2 (4×200 mL). The combined filtrates were evaporated to give 1 as a light yellow solid (19 g, 60% yield). 1H NMR (400.13 MHz, CDCl3) δ 8.37 (dd, 1H, J=4.0, 1.6 Hz, C2—H), 8.17 (dd, 1H, J=8.0, 1.6 Hz, C3—H), 7.82 (d, 1H, J=8.4 Hz, C5—H), 7.44 (t, 1H, J=7.6 Hz, C6—H), 7.40 (dd, 1H, J=8.0, 4.0 Hz, C4—H), 7.3-7.2 (m, 10H, Ph-H), 7.14 (ddd, 1H, J=7.2, 3.6, 1.6 Hz, C7—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 149.8, 149.6 (d, J=17.2 Hz), 138.4 (d, J=12.1 Hz), 137.4 (d, J=11.1 Hz), 136.2, 134.4, 134.2 (d, J=21.2 Hz), 128.8, 128.4 (d, J=19.2), 127.9, 126.57, 121.41 ppm; 31P NMR (161.97 MHz, CDCl3) δ 15.0 ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[OH:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)=[CH:11][CH:10]=1>C(O)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[O:33][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:11][CH:10]=1
Reactant: COc1ccc(B(O)C(OC(B(O)c2ccc(OC)cc2)c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)CCO
Solvent: CCO
Product: COc1ccc(B(OCCN(C)C)C(OC(B(OCCN(C)C)c2ccc(OC)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
The entitled compound (51 mg) was obtained by allowing 22 mg of N,N-dimethylethanolamine to act on 85 mg of bis(4,4′-(p-methoxyphenyl-hydroxyboryl)benzyl) ether in 0.5 mL of ethanol.
Reaction SMILES: [C:1]([N:9]1[CH:15]=[CH:14][N:13]=[CH:12][CH2:11][N:10]1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(O)C>[C:1]([N:9]1[CH2:15][CH2:14][N:13]([CH2:25][CH2:24][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:12][CH2:11][N:10]1[C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccncc1
Reactant: O=C(c1ccccc1)N1C=CN=CCN1C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CO
Product: O=C(c1ccccc1)N1CCN(CCc2ccncc2)CCN1C(=O)c1ccccc1

Procedure:
A mixture of 1,2-dibenzoyl-1H-1,2,5-triazepine (2.0 g), 4-vinylpyridine (1.42 g) and p-toluenesulfonic acid (1.21 g) in methanol (70 ml) was stirred and heated at 60° under a nitrogen atmosphere for 3 days. The foam, obtained after evaporation of the solvent, was mixed with dichloromethane and 10% sodium carbonate solution. The organic phase was washed with water until neutral washings were obtained and dried (Na2SO4). Evaporation of the solvent gave a foam, 2.25 g. The crude product was chromatographed on a column of silica gel; elution with ethanol-ethyl acetate-dichloromethane (1:4:5) giving a major component. A hydrochloride salt, 1/3 hydrate of the titled compound was formed in ethanol; wt. 1.2 g (38%), mp 247° dec.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([OH:24])=O)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:35]>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([NH2:35])=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1CC1CCCC1
Reactant: CC#N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCN(C(=O)C(N)=O)CC2)cc1CC1CCCC1

Procedure:
Following the procedure of Example 9, 2-[4-(3-cyclopentylmethyl-4-methoxyphenyl)piperidin-1-yl]-2-oxo-acetic acid (2.2 mmol, 0.750 g), oxalyl chloride (2.42 mmol, 1.21 mL; 2M solution in CH2Cl2), DMF (4 drops), and saturated NH3 /CH3CN (22 mL) in dry toluene (22 mL) afforded a solid which was purified by flash chromatography (SiO2 : 40% EtOAc/hexane) to give the title compound as a white solid, mp=117°-118° C. (1.1 mmol, 0.388 g, 51%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:15]1=[O:30])[CH3:13].[H-].[Na+]>CN(C=O)C.CO>[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:27][CH:28]=2)[C:15]1=[O:30])[CH3:13]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncccc21
Temperature: 150 °C
Yield: 82.1 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (500 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (789 mg) and NaH (132 mg) in DMF (10 ml) at room temperature. The mixture was heated at 150° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (950 mg) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCC1=O.F[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.CC(C)([O-])C.[K+]>O>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)c2ccccc21
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
1 g of 3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester, 10 ml of N-methylpyrrolidinone, 0.57 g of 4-fluorobenzonitrile and 0.96 g of potassium tert-butoxide are introduced into a 20 ml glass tube. The reaction medium is stirred for 5 min, water is added and extraction is carried out 3 times with diethyl ether. The organic phases are combined, washed with water and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluted with a gradient of ethyl acetate from 3.5% to 35% in heptane. 0.9 g of tert-butyl 4-(4-cyanophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate is obtained.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][O:49][CH2:50][CH2:51][OH:52]>CN(C)C=O>[OH:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: OCCOCCCl
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCN(CCOCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl-ester (515 mg, 1 mmol) was dissolved in dimethylformamide (3 ml). Sodium iodide (15 mg, 0.1 mmol), triethylamine (233 mg, 2.5 mmol) and 2(2-chloroethoxy)ethanol (313 mg, 3.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 18 hours at ambient temperature. The temperature was then raised to 100° C. and kept there for 1 hour. The solvent was then evaporated and the residue dissolved in a mixture of dichloromethane (4.5 ml) and trifluoroacetic acid (4.5 ml). The mixture was stirred for 2 hours at ambient temperature and the solvent was then evaporated. The residue was dissolved in water (8 ml), and this aqueous solution was washed with ether (6-4 ml). The aqueous solution was acidified and the title compound was isolated as a hygroscopic white powder after evaporation of the water. Yield 325 mg (75%), FAB MS: 435(M+1). The structure was confirmed by 1HNMR and 13C NMR.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][NH2:15])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:15][CH2:14][CH2:13][NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11]
Reactant: NCCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNCCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 74.2 %

Procedure:
A mixture of 13.7 g (59.4 mmol) of 3,5-diamino-6-chloro-N-(2-aminoethyl)pyrazine-2-carboxamide, 3.03 g (19.8 mmol) of methyl bromoacetate and 2.0 g (19.8 mmol) of triethylamine was stirred overnight in 250 ml of tetrahydrofuran at ambient temperature. The solvent was evaporated and the residue was chromatographed on silica gel (300 g) using 3.5:96.5 (v/v) methanol:methylene chloride as eluent. There was obtained 4.45 g (14.7 mmol, 74%) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]glycine methyl ester as a white powder; mp 145°-146.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[C:35](=[S:48])[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[O:5][CH2:6][CH:7]([OH:31])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[S:29])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[C:12]([OH:30])[CH:11]=1.[C:49](O)(=[O:53])[C:50]([CH3:52])=[CH2:51].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:49]([O:31][CH:7]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[S:29])[C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)=[C:12]([OH:30])[CH:11]=1)[CH2:6][O:5][C:4]1[CH:32]=[CH:33][C:34]([C:35](=[S:48])[C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:40][CH:41]=2)=[C:2]([OH:1])[CH:3]=1)(=[O:53])[C:50]([CH3:52])=[CH2:51]
Reactant: C=C(C)C(=O)O
Reactant: Oc1cc(OCC(O)COc2ccc(C(=S)c3ccc(-c4ccccc4)cc3)c(O)c2)ccc1C(=S)c1ccc(-c2ccccc2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC(COc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1)COc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
The title compound is prepared by reacting the alcohol compound of Example 12 with an excess amount of methacrylic acid in refluxing toluene in the presence of a catalytic amount of toluenesulfonic acid.
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[OH:11][CH2:12][CH:13]([CH2:19][N:20]1[CH2:24][CH:23]([CH2:25][CH2:26][CH3:27])[CH2:22][C:21]1=[O:28])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)Cl>[CH:12]([CH:13]([CH2:19][N:20]1[CH2:24][CH:23]([CH2:25][CH2:26][CH3:27])[CH2:22][C:21]1=[O:28])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11]
Reactant: CCCC1CC(=O)N(CC(CO)C(=O)OCC)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCC1CC(=O)N(CC(C=O)C(=O)OCC)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, DMSO (dried on CaH2, 0.83 g, 0.01 mol) in CH2Cl2 (5 ml) is added onto a solution of (COCl)2 (0.72 g, 0.0052 mol) in CH2Cl2 (5 ml) cooled at −78° C. After 0.5 h at −78° C., ethyl 3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoate x279 (0.92 g, 0.0035 mol) in CH2Cl2 (10 ml) is added, stirred for 2.5 h at −60° C., quenched with Et3N (2.75 ml), stirred overnight at 4° C., washed with saturated NH4Cl and extracted 3 times with CH2Cl2. The combined organic phases are dried over MgSO4, filtered, concentrated in vacuo to give the crude x280 (1.2 g) which is used in the next step without any further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:45][C:39]3[N:40]=[CH:41][N:42]=[C:43](Cl)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:45][C:39]3[N:40]=[CH:41][N:42]=[C:43]([O:21][C:18]4[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=4)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Clc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
After adding 2.97 of potassium carbonate and 30 ml of dimethylformamide to 3.09 g of 4-nitrophenol and stirring the mixture at 130° C. for 10 minutes, 2.49 g of 6-(4-benzyloxyphenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine was added and the mixture was further stirred at 130° C. for 5 hours and at 135° C. overnight. After returning the mixture to room temperature, water was added, the precipitated solid was filtered out and subjected to NH silica gel column chromatography (ethyl acetate) and silica gel column chromatography (ethyl acetate), and then ether and ethyl acetate were added prior to sonication. The solid was filtered out to obtain 1.2 g of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][OH:17].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>O1CCCC1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: CN(C)CCCO
Reactant: COc1cc(C#N)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1OCCCN(C)C
Temperature: 65 °C
Reaction time: 6 h

Procedure:
15 g 4-Fluoro-3-methoxybenzonitrile and 12 mL 3-dimethylamino-1-propanol was dissolved 150 mL tetrahydrofuran. 21.7 g Potassium hexamethyldisilazide was added and the mixture was stirred at 65° C. for 6 h. the mixture was concentrated to 50 mL and the residue diluted in ethyl acetate, washed with water and saturated sodium chloride solution and the organic phase dried over magnesium sulfate.