Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:35])NC1SC(C2C=CC=C(C(=O)NC3CC3)C=2)=CN=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]([C:40]1[S:44][C:43]([NH2:45])=[N:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([C:52](=[O:57])[NH:53][CH:54]2[CH2:56][CH2:55]2)=[CH:48][CH:47]=1)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(OC(N1CCC[C@H]1C(O)=O)=O)C1C=CC=CC=1>>[CH3:36][O:37][C:38]([C:40]1[S:44][C:43]([NH:45][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[O:35])=[N:42][C:41]=1[C:46]1[CH:47]=[CH:48][C:49]([C:52](=[O:57])[NH:53][CH:54]2[CH2:56][CH2:55]2)=[CH:50][CH:51]=1)=[O:39]
Reactant: COC(=O)c1sc(N)nc1-c1ccc(C(=O)NC2CC2)cc1
Reactant: O=C(NC1CC1)c1cccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)nc1-c1ccc(C(=O)NC2CC2)cc1

Procedure:
In a similar procedure as described for the synthesis of Compound 5312 (Example 312), 2-amino-4-(4-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid methyl ester (0.098 g, 0.31 mmol) was treated with HATU (0.18 g, 0.46 mmol), DIEA (0.3 mL, 2.3 mmol), and (S)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.12 g, 0.46 mmol) to furnish the desired product. 1HNMR (DMSO-d6) δ(ppm)12.90-12.88 (d, 1H), 8.89-8.85 (m, 1H), 8.51-8.50 (d, 1H), 7.86-7.72 (m, 4H), 7.37-7.33 (m, 2H), 7.15-7.09 (m, 2H), 5.09-4.87 (m, 2H), 4.51-4.49 (m, 1H), 3.74-3.72 (m, 3H), 3.53-3.47 (m, 1H), 2.88-2.84 (m, 1H), 2.45 (m, 1H), 1.91-1.87 (m, 3H), 0.71-0.59 (m, 4H); MS: 549.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1>>[ClH:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH:28][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH:21]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCc1cccnc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCc3cccnc3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 31 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-pyridin-3-yl-ethylamine as described in Steps 5 and 6, Example 24 to give the title compound as a cream-yellow solid (31% yield). LC/MS: RT 2.02 min, m/e 404 (M+H); 1H NMR (δ, ppm): 11.85 (1H, s), 8.79-8.82 (2H, m), 8.47 (1H, d), 7.98-8.08 (2H, m), 7.52 (1H, dd), 7.33 (1H, s), 7.15 (1H, dd), 3.25 (2H, dt), 2.98 (2H, t), 2.41 (2H, q), 2.31 (3H, s), 1.10 (3H, t).
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([OH:13])=[O:12].C(OCC1CSC2N(C(=O)C2N)C=1C(O)=O)(=O)C.CC1CSC2N(C(=O)C2NC(=O)C(C2C=CC(CCl)=CC=2)N)C=1C(O)=O.[C:59]([O:65][CH2:66][O:67][C:68]([C:70]1[N:71]2[CH:74]([S:75][CH2:76][C:77]=1[CH3:78])[CH:73]([NH:79]C(=O)C(C1C=CC(CCl)=CC=1)N)[C:72]2=[O:92])=[O:69])(=[O:64])[C:60](C)(C)C>>[C:68]([O:67][CH2:66][O:12][C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[CH3:14])[CH:2]([NH2:1])[C:9]2=[O:10])=[O:13])(=[O:69])[CH2:70][CH2:77][CH3:76].[C:59]([O:65][CH2:66][O:67][C:68]([C:70]1[N:71]2[CH:74]([S:75][CH2:76][C:77]=1[CH3:78])[CH:73]([NH2:79])[C:72]2=[O:92])=[O:69])(=[O:64])[CH3:60]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(N)c3ccc(CCl)cc3)C2SC1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(CCl)cc3)C2SC1
Product: CC(=O)OCOC(=O)C1=C(C)CSC2C(N)C(=O)N12
Product: CCCC(=O)OCOC(=O)C1=C(C)CSC2C(N)C(=O)N12

Procedure:
When in the procedure of Example 16 an appropriate amount of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid or the corresponding pivalyloxymethyl ester is substituted for 3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-methyl-7-[[2-[4-(chloromethyl)-phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid and 3-methyl-7-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivalyloxymethyl ester are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[C:14](=[O:16])[N:13]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:25]([O:35]C([O-])=O)(=O)[O:26][CH:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:30][CH2:29][CH2:28][CH:27]([O:26][C:25]([N:13]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:11]2[C:15](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:25]([O:26][CH:27]([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])=[O:35])[C:10]2=[O:24])[C:14]1=[O:16])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: O=c1nc(-c2ccc(Cl)cc2)c2c(=O)nc(-c3ccc(Cl)cc3)c1=2
Reactant: CCCC(CCC)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCC(CCC)OC(=O)N1C(=O)C2=C(c3ccc(Cl)cc3)N(C(=O)OC(CCC)CCC)C(=O)C2=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 49.2 %

Procedure:
2.14 g of 3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione (Pigment Red 254), 7.26 g of 4-heptyl pyrocarbonate from Example B1, 0.30 g of 4-dimethylaminopyridine and 150 ml of dry tetrahydrofuran are mixed and the mixture is stirred at room temperature for 165 minutes. The suspension is filtered through a glass microfilter supporting a cotton filter, the solvent is evaporated off under reduced pressure and the residue is admixed with 50 ml of isopropanol. After 16 hours the precipitate is filtered off with suction and dried under reduced pressure to leave 1.90 g (49% of theory) of 2,5-di-4-heptyloxycarbonyl-3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione as orange crystals. NMR (CDCl3) [ppm]: δ=7.67 (d,4H), 7.46 (d,4H), 4.98 (m,2H), 1.55 (m,8H), 1.30 (m,8H), 0.90 (t,6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:10].[H][H]>[Pd].CO>[ClH:10].[OH:9][C:5]1[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: N#Cc1cccc(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccc(O)c1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Methanol (100 mL) and 10% palladium on carbon (2 g) were charged to a 250 mL Parr bottle followed by 3-cyanophenol (19.0 g, 0.1595 mol) and concentrated HCl (16.66 mL, 0.2 mol). The mixture was hydrogenated at room temperature and 50 psi until the uptake of hydrogen stopped (about 10 h). The reaction was filtered through a bed of Celite and the filter cake was washed with methanol (3×25 mL). The combined filtrates were evaporated under reduced pressure. Remaining volatiles were removed by evaporating the residue twice from 50 mL portions of absolute ethanol. The crude amine hydrochloride, essentially free of residual HCl, was dissolved with warming in a minimum amount of absolute ethanol (˜80 mL) and the stirred solution was diluted with anhydrous diethyl ether (500 mL). The mixture was stirred in an ice bath for 1 h then the colorless crystalline product was filtered off, washed with anhydrous diethyl ether (3×50 mL) and dried in vacuo to furnish (3-hydroxyphenyl)methylamine hydrochloride salt (20.6 g, 80.9%), mp 146-148° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:33][CH:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NC1CCOCC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 27.5 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-aminotetrahydropyran (available from Aldrich Chemical Company, Inc.; 63 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(tetrahydro-pyran-4-ylcarbamoyl)-biphenyl-2-carboxylic acid (32 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (br s, 1H), 8.39 (s, 1H), 8.25-8.33 (m, 3H), 8.17 (dd, J=8.0, 1.8 Hz, 1H), 8.02 (dd, J=8.3, 2.0 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 3.91-4.03 (m, 1H), 3.83 (d, J=9.8 Hz, 2H), 3.30-3.38 (m, 2H), 1.68-1.76 (m, 2H), 1.54 (qd, J=11.9, 4.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[NH2:22])=[S:7])=[O:4].[CH2:23]([O:25][C:26]([NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])=[CH:34][C:33]=1[NH2:45])=[S:30])=[O:27])[CH3:24].COC(NC(NC1C=CC(CCCC)=CC=1N)=S)=O>>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][CH:19]([CH3:20])[CH3:21])=[O:17])=[CH:11][C:10]=1[NH:22][C:23](=[O:25])[CH3:24])=[S:7])=[O:4].[CH2:23]([O:25][C:26]([NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])=[CH:34][C:33]=1[NH:45][C:19](=[O:18])[CH3:20])=[S:30])=[O:27])[CH3:24]
Reactant: CCOC(=O)NC(=S)Nc1ccc(NC(=O)OC(C)C)cc1N
Reactant: COC(=O)NC(=S)Nc1ccc(NC(=O)OC(C)C)cc1N
Agent: CCCCc1ccc(NC(=S)NC(=O)OC)c(N)c1
Product: CCOC(=O)NC(=S)Nc1ccc(NC(=O)OC(C)C)cc1NC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(NC(=O)OC(C)C)cc1NC(C)=O

Procedure:
By proceeding in a similar manner but substituting an equimolecular quantity of 1-methoxycarbonyl-3-(2-amino-4-isopropoxycarbonylaminophenyl)thiourea and 1-ethoxycarbonyl-3-(2-amino-4-isopropoxycarbonylaminophenyl)thiourea for 1-methoxycarbonyl-3-(2-amino-4-n-butylphenyl)thiourea, there were obtained 1-methoxycarbonyl-3-(2-acetamido-4-isopropoxycarbonylaminophenyl)thiourea, m.p. 187°-188° C. (with decomposition) and 1-ethoxycarbonyl-3-(2-acetamido-4-isopropoxycarbonylaminophenyl)thiourea, m.p. 201°-202° C. (with decomposition), respectively.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[ClH:12].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([NH:21][C:22]([C:24]1[S:25][C:26]3[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][OH:40])=[CH:31][CH:30]=[CH:29][C:27]=3[CH:28]=1)=[O:23])[CH2:14]2.C1COCC1>CN(C=O)C>[ClH:12].[CH3:8][NH:9][C:10](=[O:11])[O:40][CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]1[C:26]2[S:25][C:24]([C:22]([NH:21][C@@H:15]3[CH:16]4[CH2:17][CH2:18][N:13]([CH2:20][CH2:19]4)[CH2:14]3)=[O:23])=[CH:28][C:27]=2[CH:29]=[CH:30][CH:31]=1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3CO)c2s1
Reactant: CN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)OCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
32.5 μl (0.23 mmol) of triethylamine and 13.3 mg (0.23 mmol) of methyl isocyanate are added to a suspension of 50 mg (0.12 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride (Example 131) in 1 ml of a 5:1 mixture of THF and DMF. After 18 h at room temperature, a further 13.3 mg (0.23 mmol) of methyl isocyanate and a catalytic amount of 4-N,N-dimethylaminopyridine are added. The mixture is stirred at room temperature for a further 18 h. The reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 18 mg (30% of theory) of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[CH2:22]([O:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1C(Cl)=O)[CH3:23].[CH2:38]([N:40]1[C:52]2[CH:51]=[CH:50][C:49]([NH2:53])=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH3:39]>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:33]=[CH:34][C:25]=2[O:24][CH2:22][CH3:23])=[O:7])[C@H:9]([C:19]([NH:53][C:49]2[CH:50]=[CH:51][C:52]3[N:40]([CH2:38][CH3:39])[C:41]4[C:46]([C:47]=3[CH:48]=2)=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCOc1ccc2ccccc2c1C(=O)N1CC(=NOC(C)(C)C)C[C@H]1C(=O)Nc1ccc2c(c1)c1ccccc1n2CC

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, 2-ethoxy-1-naphthoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=591.4.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].N1C=CC=CC=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([NH:11][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1c(O)cccc1C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Thionyl chloride (25 mL) was added to 3-nitrobenzoic acid (3 g, 18.0 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure to give a residue which was dried in vacuum to obtain a yellow solid of 4-nitrobenzoyl chloride. 3-Hydroxyanthranilic acid (0.92 g, 6.0 mmol) and pyridine (1.45 mL, 18.0 mmol) were added to toluene (30 mL) and the mixture was stirred at room temperature for 30 min. 4-nitrobenzoyl chloride (3.34 g, 18.0 mmol) was then added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. Evaporated the solvents under reduced pressure and the residue was washed with 5% aqueous hydrochloric acid (100 mL×3), filtered, and washed with water (100 mL×3), dried in vacuum at 50° C. to obtain 3-hydroxy-2-(4-nitrobenzamido)benzoic acid (1.8 g, yield 100%) as a yellow solid. MS (ESI) m/z 303 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9](F)=[CH:10][CH:11]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]2=[O:26])=[CH:4]1)[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][OH:34].[H-].[Na+]>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([O:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]2=[O:26])=[CH:4]1)[CH3:2]
Reactant: OCc1ccccn1
Reactant: CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(F)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a stirred solution of tert-butyl 4-(1-ethyl-6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopiperazine-1-carboxylate (5.00 g, 13.80 mmol) and 2-pyridine methanol (1.60 mL, 16.56 mmol) in dimethyl sulphoxide (50 mL), under a nitrogen atmosphere, is added 60% sodium hydride (0.662 g, 16.56 mmol) portionwise. The reaction is stirred at room temperature for 1 h and then heated at 135° C. overnight. The reaction is cooled to room temperature and further 60% sodium hydride (0.662 g, 16.56 mmol) added, and the reaction stirred overnight at room temperature. The reaction is poured onto brine (ca. 500 mL) and the product extracted with CHCl3 (ca. 2×300 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 80% EtOAc in DCM, to give the title compound as an orange foam (4.952 g, 10.97 mmol). MS (m/z): 452 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([CH:25]([NH2:27])[CH3:26])=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)[CH:12]=[C:13]([F:15])[CH:14]=1.Br[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([CH:25]([NH:27][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:26])=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: CC(N)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1ncnc2[nH]cnc12)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Temperature: 110 °C
Yield: 11.3 %

Procedure:
1-[3-(3,5-Difluorophenyl)pyrazolo[1,5-a]pyridin-2-yl]ethanamine trifluoroacetate (16 mg, 0.07 mmol), 6-bromo-9H-purine (13 mg, 0.07 mmol, Aldrich 104981) and N,N-diisopropylethylamine (12 mL, 0.07 mmol) were stirred in ethanol (0.47 mL) and heated to 110° C. for 16 hours. Purification by preparative LCMS (H2O with 0.1% TFA (pH 2), 5% acetonitrile to 24% acetonitrile over 1 minute, 24% to 48% acetonitrile over 12 minutes, Waters Sunfire C18, 5 μM particle size, 30×100 mm, RT=8.75 min.) gave the desired compound (4.0 mg, 12%). LCMS for C20H17F2N7 (M+H)+: m/z=392.0. 1H NMR (300 MHz, DMSO-d6): δ 8.75 (m, 1 H), 8.39 (m, 1 H), 8.28 (m, 1 H), 7.64 (m, 1 H), 7.31 (m, 1 H), 7.23 (m, 2 H), 7.17 (m, 1 H), 6.98 (m, 1 H), 5.84 (m, 1 H), 1.62 (m, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:18][CH2:19][CH3:20])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:21])[CH:5]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH:10]1[C:9]2([CH2:18][CH2:19][CH3:20])[C:4](=[CH:5][C:6](=[O:21])[CH2:7][CH2:8]2)[C:3]2[C:11]1=[CH:12][C:13]([O:16][CH3:17])=[C:14]([Cl:15])[C:2]=2[Cl:1]
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2Br
Yield: 91.6 %

Procedure:
A mixture of 5,6-dichloro-1,2,9,9a-tetrahydro-7-methoxy-9a-propyl-3H-fluoren-3-one (3.25 g, 0.01 mol), N-bromosuccinimide (1.78 g, 0.01 mole) and benzoyl peroxide (75 mg) in carbon tetrachloride (50 ml) was heated at reflux for 13/4 hours, cooled, filtered and the CCl4 distilled at reduced pressure to give 3.70 g 9-bromo-5,6-dichloro-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one which melted at 131.5°-133.5° C. after crystallization from diethyl ether.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)=[N:12][N:13]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[OH:27])[CH3:2].[CH2:28]([C@@H:30]1[O:32][CH2:31]1)Cl.[NH3:33]>CO>[NH2:33][CH2:28][C@H:30]([OH:32])[CH2:31][O:27][C:4]1[C:5]([CH3:26])=[CH:6][C:7]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)=[N:12][N:13]=2)=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: N
Reactant: CCc1cc(-c2nnc(-c3cc(C)cc(CN(C)CC)c3)o2)cc(C)c1O
Reactant: ClC[C@H]1CO1
Solvent: CO
Product: CCc1cc(-c2nnc(-c3cc(C)cc(CN(C)CC)c3)o2)cc(C)c1OC[C@@H](O)CN

Procedure:
The title compound was prepared in analogy to Example 128 starting from the compound of Example 153 using (R)-epichlorohydrine in step a) and ammonia in methanol in step b). LC-MS: tR=0.65 min; [M+1]+=439.20.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CC(C)=O.O>[CH2:20]([O:19][C:17](=[O:18])[NH:11][C:7]1[N:6]=[C:5]2[O:4][CH2:3][CH2:2][O:1][C:10]2=[CH:9][CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2c(n1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc2c(n1)OCCO2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 2,3-dihydro-1,4-dioxino[2,3-b]pyridin-6-amine (commercial; 2.70 g) in acetone/water 1:1 (40 mL) was treated at 0° C. with 1M NaHCO3 (35 mL) and CbzCl (2.63 mL). The reaction mixture was stirred at rt for 3 h, the org. solvent was evaporated under reduced pressure and the residue was partitioned between water and ether/EA. The org layer was dried over MgSO4 and evaporated under reduced pressure, affording a beige solid (5.3 g; 100% yield).
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:29])[C:12]([OH:28])=[C:13]([C:15]3[O:16][C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:18][N:19]=3)[N:14]=[C:3]21.[CH3:30][N:31]([CH3:37])[C:32](=[O:36])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:17]2[O:16][C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:33](=[O:34])[C:32]([N:31]([CH3:37])[CH3:30])=[O:36])[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]5)[CH2:5][N:4]4[C:11](=[O:29])[C:12]=3[OH:28])=[N:19][N:18]=2)=[CH:22][CH:23]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: NC12CCC(CC1)Cn1c2nc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.64 %

Procedure:
To a solution of 10-amino-2-(5-(4-fluorobenzyl)-1,3,4-oxadiazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Intermediate 12 (20 mg, 0.042 mmol) in DMF (1.5 mL) was added 2-(dimethylamino)-2-oxoacetic acid (9.79 mg, 0.084 mmol), N,N-dissopropylethylamine (0.044 mL, 0.251 mmol), HATU (31.8 mg, 0.084 mmol) and DMAP (5.11 mg, 0.042 mmol) and the resulting mixture stirred at room temp for 3 h and then purified by preparative HPLC to afford the title compound (5 mg, 9.47 μmol, 22.64% yield) as a purple solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.10 (1H, br. s.), 9.60 (1H, s), 7.54 (2H, dd, J=8.39, 5.34 Hz), 7.10 (2H, t, J=8.55 Hz), 4.35 (2H, s), 4.24 (2H, br. s.), 3.44 (3H, s), 3.13 (3H, s), 2.99-3.08 (3H, m), 2.54 (1H, br. s.), 2.03-2.13 (2H, m), 1.85-1.94 (2H, m), 1.72-1.81 (2H, m). LCMS (M+H)+=497.18.