Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([NH:19][O:20][CH:21]([CH3:23])[CH3:22])[CH3:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:19]([CH2:17][CH3:18])[O:20][CH:21]([CH3:23])[CH3:22])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CCNOC(C)C
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(CC)OC(C)C)n1
Yield: 88 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with N-ethyl-O-isopropyl-hydroxylamine hydrochloride (LXXV) as described in Example 13, yielding N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI) (88% yield). ESI-MS (m/z): 297 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:46]=[C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][C:54]5[CH2:59][CH2:58][C:57]([CH3:61])([CH3:60])[CH2:56][C:55]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:49][CH2:48]4)[CH:44]=[CH:43][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]([CH:37]4[CH2:39][CH2:38]4)C(=O)OC(C)(C)C)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[Cl:68][C:65]1[CH:64]=[CH:63][C:62]([C:55]2[CH2:56][C:57]([CH3:60])([CH3:61])[CH2:58][CH2:59][C:54]=2[CH2:53][N:50]2[CH2:51][CH2:52][N:47]([C:45]3[CH:44]=[CH:43][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][NH:29][CH:37]5[CH2:38][CH2:39]5)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:46]=3)[CH2:48][CH2:49]2)=[CH:67][CH:66]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCCCN(C(=O)OC(C)(C)C)C5CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCCCNC5CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 291D (2.56 g) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred for 2 hours. The mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (300 mL) and washed with aqueous NaHCO3, water, and brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product. The title compound was obtained by dissolving 200 mg of the crude material in dimethylsulfoxide/methanol (1:1, 10 mL) and loaded on Gilson, C18(100A) 250×121.2 mm (10 micron), eluting with 30% acetonitrile to 65% acetonitrile over 40 minutes. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.54 (s, 1H), 8.43 (m, 2H), 7.94 (d, 1H), 7.71 (dd, 1H), 7.57 (d, 1H), 7.43 (m, 1H), 7.34 (m, 3H), 7.05 (d, 2H), 6.90 (d, 1H), 6.63 (dd, 1H), 6.29 (d, 2H), 3.43 (m, 2H), 2.96 (m, 6H), 2.73 (m, 2H), 2.22 (m, 7H), 1.87 (m, 4H), 1.38 (m, 3H), 0.94 (m, 6H), 0.62 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1csc(-c2ccc(F)cc2)n1
Product: O=C(NCCc1csc(-c2ccc(F)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 45 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 45%). 1H NMR (400 MHz, CDCl3) δ 8.53 (t, J=1.4 Hz, 1H), 8.27-8.24 (dt, J=7.9 Hz, 1.3 Hz, 1H), 8.09-8.06 (dt, J=7.6 Hz, 1.6 Hz, 1H), 7.94-7.90 (m, 2H), 7.70 (m, 1H), 7.63-7.59 (t, J=7.8 Hz, 1H), 7.09-7.05 (m, 3H), 3.91-3.86 (m, 2H), 3.16-3.13 (t, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C21H14F4N4O2S: 462.08. found: 463.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[C:42]([CH3:47])=[CH:43][CH:44]=[CH:45][CH:46]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH3:47])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Cc1ccccc1N
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (146 mg, 0.428 mmol), EDC (115, 0.599 mmol), and HOBT (81 mg, 0.599 mmol) in DMF (8 mL) was added o-toluidine (64 mg, 0.60 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (92 mg) as a yellow solid. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:19][CH:21]2[CH2:22][O:23]2)=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: BrCC1CO1
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)ccc1OCC1CO1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A solution of N-(5-Chloro-2-hydroxy-phenyl)-acetamide (0.499 g, 2.68 mmol), K2CO3 (0.60 g, 4.35 mmol) and epibromohydrin (0.405 g, 2.95 mmol) in DMF (5 ml) was heated with stirring at 50° C. for 2 hours. The mixture was then partitioned between EtOAc and water 40+40 ml. The organic phase was washed twice with water and once with brine and finally concentrated in vacuo to give a crude product. The crude product was purified on silica (heptane:EtOAc, 1:1), to give 0.43 g (66%) of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.[CH2:16]([CH2:22]Cl)[CH2:17][O:18][C:19](Cl)=[O:20].CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH2:22][CH2:16][CH2:17][O:18][C:19]2=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)OCCCCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1OCCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a mixture of p-nitroaniline (0.50 g, 0.0036 mol) and 4-dimethylaminopyridine (DMAP, 0.531 g, 0.00434 mol) in tetrahydrofuran (10 mL, 0.1 mol) was added 3-chloropropyl chloridocarbonate (0.480 mL, 0.00398 mol). The mixture was stirred at room temperature for 1 h, then treated with 1.0 M of potassium tert-butoxide in tetrahydrofuran (7.96 mL, 0.00796 mol) at room temperature for 2 h, then quenched with aqueous ammonium chloride, extracted with EtOAc. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to provide the product (260 mg, 32.32%). LCMS (M+H) 222.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].Br[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:9]
Reactant: O=C(c1ccc(-c2cc(Cl)ccc2O)cc1Cl)N1CCCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCC2)c(Cl)c1
Reaction time: 16 h

Procedure:
The product from step c) (180 mg), tert-butyl bromoacetate (0.07 ml), potassium carbonate (0.1 g) and DMF (10 ml) were charged to a flask and stirred for 16 h. Water was added and then washed with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (8:2). The sub-title compound was dissolved in DCM (8 ml) and TFA (2 ml) was added, stirred for 1 h, then concentrated in vacuo. Trituration with a mixture of ether and isohexane gave a solid, which was further purified by reverse phase HPLC to give the title compound. Yield (48 mg)
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:33][CH2:34][CH3:35])[C:9](=[O:32])[NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)(=[O:21])=[O:20])[CH2:17]2)[CH2:13][CH2:12]1)(C)(C)C.C(N1C[C@@H]2[C@@H](NC(=O)[C@@H](N(C)C(=O)OC(C)(C)C)CC(C)C)CC[C@@H]2C1)C1C=CC=CC=1>>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([S:19]([N:16]2[CH2:17][C@H:18]3[C@H:11]([NH:10][C:9](=[O:32])[C@H:8]([CH2:33][CH2:34][CH3:35])[NH2:7])[CH2:12][CH2:13][C@H:14]3[CH2:15]2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Agent: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Product: CCC[C@H](N)C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting tert-butyl-((S)-1-oxo-1-((3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate was prepared by substituting tert-butyl-((S)-1-oxo-1-((3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate from Step A for tert-butyl(S)-1-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate in the procedure described in Example 348: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.35-8.37 (m, 1H), 8.27 (d, J=7.0 Hz, 1H), 8.17-8.19 (m, 1H), 7.90-7.92 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 4.18-4.25 (m, 1H), 3.84 (dd, J=9.9, 2.7 Hz, 1H), 3.51 (dd, J=7.9, 4.9 Hz, 1H), 3.17 (dd, J=9.6, 2.8 Hz, 1H), 3.07 (dd, J=9.9, 7.6 Hz, 1H), 2.91 (dd, J=9.6, 7.3 Hz, 1H), 2.43-2.54 (m, 2H), 1.96-2.32 (m, 2H), 1.87-1.95 (m, 2H), 1.78-1.84 (m, 1H), 1.59-1.67 (m, 1H), 1.37-1.53 (m, 3H), 1.23-1.32 (m, 1H), 0.83 (t, J=7.3 Hz, 3H); MS (ESI−) m/z 432 (M−H)−.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]1[CH:40]=[C:39]([F:41])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:12]([F:42])[CH:11]=1.O=C1CCC(=O)N1[O:50][C:51](=O)[CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH:66][C:67](=[O:77])[CH2:68][CH2:69][N:70]1[C:74](=[O:75])[CH:73]=[CH:72][C:71]1=[O:76].CCN(C(C)C)C(C)C>>[O:76]=[C:71]1[CH:72]=[CH:73][C:74](=[O:75])[N:70]1[CH2:69][CH2:68][C:67]([NH:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([F:42])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:39]([F:41])[CH:40]=1)=[O:50])=[O:77]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CN)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid TFA salt (120 mg, 0.2 mmol), 3-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (103 mg, 0.2 mmol), and DIPEA (129 mg, 174 uL, 1.0 mmol), and after HPLC purification, resulted in a white solid (75 mg, 43%). ES(+)-HRMS m/e calcd. for C42H50F2N6O13 (M+Na)+ 907.3296, obsd. 907.3296.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1NCCc1ccccc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1NCCc1ccccc1

Procedure:
By substituting 3-nitro-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid Example 9 B, the above compound was obtained with a melting point of 194°-195°C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]([Cl:23])[N:8]=1)C.O.[OH-].[K+].Cl>C(O)CO>[Cl:23][C:9]1[N:8]=[C:7]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:13][C:12]2=[CH:11][CH:10]=1
Reactant: CCOC(=O)CNc1nc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Temperature: 0 °C
Yield: 26.9 %

Procedure:
A solution of N-[6-chloro-3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (1.7 g, 0.00462 mole) in ethylene glycol (25 ml) was refluxed under nitrogen for two hours. To one-half of the solution (0.0023 mole) was added water (2 ml) and solid potassium hydroxide (0.20 g, 0.003515 mole) and the mixture was refluxed for an additional 15 minutes, poured into ice water (100 ml) and acidified with 3 N hydrochloric acid solution. The resulting solid was collected by filtration, rinsed with water, dissolved in hot methanol and filtered hot. Addition of water to the collected by filtration, washed with water, and dried at 60° C. under high vacuum to give 0.4 g (54% yield) of title compound, mp >250° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][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][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[N+:36]=[N-:37])[CH:30]=1)=[O:28])C.N(C1C=C(C=CC=1)C(Cl)=O)=[N+]=[N-]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[N+:36]=[N-:37])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(N=[N+]=[N-])c1
Agent: [N-]=[N+]=Nc1cccc(C(=O)Cl)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1cccc(N=[N+]=[N-])c1

Procedure:
Prepared (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (569 mg, 2 mmol) and 3-(3-azido-phenyl)-3-oxo-propionic acid ethyl ester (700 mg, 3 mmol; prepared from 3-azido-benzoyl chloride (Bioorg. Chem 1986, 134) using the procedure described in Synthesis, 1993, 290, method A, MS (EI) 233 (M+)) according to the general procedure K. Obtained as an orange solid (367 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.Cl[C:13]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][C:13]3[N:18]=[N:17][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:15]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=4)[CH:14]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Reactant: Cc1nc2cc(O)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(-c4ccccc4)nn3)ccc2s1

Procedure:
The title compound was prepared analogous to the procedure used to prepare Example 45(f), using 2-methyl-5-benzothiazolol (117 mg, 0.7 mmol, Aldrich), 6-chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 13 (e)), (197 mg, 0.6 mmol) and NaH (37 mg, 0.9 mmol, 60% suspension in mineral oil, Aldrich) in DMF (5 mL). Purification by flash silica gel chromatography with 2M NH3 in MeOH/CH2Cl2 (0:1→1:49) as eluant gave the title compound as a pale-orange amorphous solid. Mp: 208–209° C. MS (ESI, pos ion.) m/z: 464 (M+1).
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[N:23]=[C:22]2[N:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]([NH2:27])=[N:26][C:21]2=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:5]1[O:6][C:7]([C:18]2[N:23]=[C:22]3[N:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]([NH2:27])=[N:26][C:21]3=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(N)nc2ccc(Br)nc21
Reactant: CC(C)(C)c1nc(-c2ccc(F)cc2)co1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N)nc2ccc(-c3oc(C(C)(C)C)nc3-c3ccc(F)cc3)nc21
Temperature: 25 °C
Yield: 26 %

Procedure:
Bubble with nitrogen a suspension of 2-tert-butyl-4-(4-fluorophenyl)oxazole (0.145 g, 0.66 mmol), 5-bromo-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine (0.355 g, 1.32 mmol), cesium carbonate (6.06 g, 18.6 mmol), palladium (II) acetate (0.201 g, 10%) and triphenylphosphine (0.14 g, 0.07 mmol) in DMF (1.5 mL). Heat the reaction at 100° C. overnight, cool to RT and partition between EtOAc and saturated aqueous NaCl. Wash the organic layer with saturated aqueous NaCl. Dry with Na2SO4, filter, concentrate, and purify (silica gel chromatography, eluting with 2% of 2M ammonia/MeOH in CH2Cl2 to give the title compound (0.07 g, 34%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].BrCC(C1C=CC(C2C=CC(F)=CC=2F)=CC=1)=O.[C-:36]#[N:37].[K+]>>[C:36]([CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)=[O:3])#[N:37]
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: [C-]#N
Agent: O=C(CBr)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Product: N#CCC(=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Grignard reagent obtained from 14.2 g. of methyl iodide and 2.4 g. of magnesium in 100 ml. of THF is added dropwise to a solution of 30.4 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-oxopropionic acid ethyl ester, obtained by brominating 4-acetyl-2',4'-difluorobiphenyl to 4-bromoacetyl-2',4'-difluorobiphenyl, reacting this with KCN to give 4-cyanoacetyl-2',4'-difluorobiphenyl, hydrolyzing the latter and esterifying the reaction product, in 200 ml. of THF. When the addition is complete, the mixture is heated and stirred for 2 hours more on a water bath and cooled. The resulting alcoholate is hydrolyzed with ice and saturated NH4Cl solution. The ether phase is dried and evaporated to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, m.p. 96°-97°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11]COC.FC1C=CC2[B:23](O)[O:22]CC=2C=1>>[OH:22][B:23]1[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[CH2:10][O:11]1
Reactant: COCOCc1cc(OC)ccc1Br
Reactant: OB1OCc2cc(F)ccc21
Product: COc1ccc2c(c1)COB2O

Procedure:
This compound was made from 18g in the same manner as compound 19b: mp 102-104° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 3.77 (s,3H), 4.91 (s, 2H), 6.88 (d, J=8.1 Hz, 1H), 6.94 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 8.95 (s, 1H); ESI-MS m/z 163 (M−H)−; HPLC purity 100%; Anal (C8HgBO3) C, H.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:15])SC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](#[N:18])[CH3:17]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([N:18]1[CH2:5][CH2:4][CH:3]([CH2:2][CH2:1][OH:8])[CH2:17][CH2:16]1)=[NH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CCO)CC1
Yield: 41 %

Procedure:
(0.028 mol) of N-benzyloxycarbonyl-S-methyl isothiourea in 50 ml of acetonitrile was refluxed overnight. Evaporation and flash chromatography on silica gel with ethyl acetate gave 3.5 g (41%) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([PH:20](=[O:22])[OH:21])[NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=[C:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>C(OCC)(=O)C.O>[OH:22][P:20]([CH:8]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH2:23][CH:24]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:21]
Reactant: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)OC
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccccc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 67 %

Procedure:
A solution of 1 g (3.31 mmol) of [2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinic acid, 0.66 g (3.75 mmol) of methyl α-methylenebenzenepropanoate and 3.1 ml of N,O-bis(trimethylsilyl)acetamide is maintained at 60° C. for 24 hours. After cooling, 60 ml of a 1/1 ethyl acetate/water mixture are added. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated under vacuum. The residue is purified by recrystallization from a mixture of ethyl acetate and hexane. 1.04 g of product are recovered (yield=67%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:20](=[O:34])[N:19]2[CH3:35])=[CH:11][C:10]=1I)([CH3:7])[CH3:6])[CH3:2].[CH2:38](B(O)O)[CH2:39][CH2:40][CH3:41]>>[CH2:1]([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:20](=[O:34])[N:19]2[CH3:35])=[CH:11][C:10]=1[CH2:38][CH2:39][CH2:40][CH3:41])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1I
Reactant: CCCCB(O)O
Product: CCCCc1cc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OCC

Procedure:
The titled compound is prepared, according to the procedure of Example 3, Step B, using 2-(2-Iodo-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester (0.270 g, 0.430 mmole) and n-butyl boronic acid (0.218 g, 0.215 mmole) to produce an oil (0.115 g, 48%). Mass [EI+] 563 (M+H)+.