Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:32]5[CH2:31][CH2:30][NH:29][CH:28]([CH3:27])[CH2:33]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: CC1CNCCN1
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCNC(C)C4)c(F)cc3cc2c1=O

Procedure:
The (RS)-1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 35 but starting from 1.8 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 2 g of (RS)-2-methylpiperazine. After recrystallizing once from 15 cm3 of propan-2-ol and 15 cm3 of diisopropyl ether, 1.9 g of (RS)-1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 190° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].Cl.CN.[CH2:17]([NH:21]C(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CCC1C(OC)=O)=O)CCC>>[CH3:17][NH:21][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1c2ccccc2CCC1C(=O)OC)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cnc2ccccc2n1
Agent: CN
Agent: Cl
Product: CNC(=O)c1cnc2ccccc2n1

Procedure:
is obtained starting from 0.5 g of 2-quinoxaloyl chloride by reaction with methylamine hydrochloride under customary reaction conditions: Rf (P)=0.69.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH2:19])[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH:19][C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=1)[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@@H](N)Cc2cccc(C)c2)c1
Reactant: OB(O)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)Nc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-L-phenylalaninamide (0.6 g, 1.42 mmol) in CH2Cl2 (15 mL) is added 4-fluorophenylboronic acid (0.398 g, 2.85 mmol), cupric acetate (0.26 g, 1.4 mmol) and pyridine (0.23 mL, 2.85 mmol), and the dark blue solution is stirred overnight at room temp. The solution is then diluted with CH2Cl2 (35 mL), and washed with 1 N HCl (50 mL) and brine (50 mL), then dried (MgSO4), evaporated and chromatographed (silica, 30% EtOAc/hexane) to yield N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-(4-fluorophenyl)-L-phenylalaninamide, as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:1][C:2]1[N:3]=[C:4]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(OCC4CC4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc(OCC2CC2)c2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a suspension of 62 (570 mg, 1.18 mmol) in MeOH was added K2CO3 (50 mg, 0.36 mmol) at room temperature. The reaction mixture was stirred 1 h, concentrated, partitioned between 20% IPA-CHCl3 and water, and then triturated with Et2O to afford 128 mg (29%) of 63 as a white solid: 1H (400 MHz, d6-DMSO) δ 6.86 (s, 2H), 5.85 (d, J=5.1 Hz, 1H), 5.27 (d, J=5.5 Hz, 1H), 4.96 (d, J=5.5 Hz, 1H), 4.77 (q, J=5.5 Hz, 1H), 4.66 (t, J=5.9 Hz, 1H), 4.18 (dd, J=7.3, 1.1 Hz, 1H), 4.09 (q, J=5.5 Hz, 1H), 3.75 (q, J=5.1 Hz, 1H), 3.39-3.60 (m, 2H), 1.20-1.27 (m, 1H), 0.53-0.57 (m, 2H), 0.31-0.34 (m, 2H); MS (+)-ES [M+H]+ m/z 371. Elemental Analysis calc'd for C14H18N4O6S: C, 45.40; H, 4.90; N, 15.13; S, 8.66. Found: C, 44.98; H, 4.92; N, 14.92; S, 8.49.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([Li])CCC.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH:25]=O.O>CCCCCC>[F:21][C:22]1[CH:23]=[C:24](/[CH:25]=[C:6](\[CH3:7])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)/C(C)=C/c1cc(F)cc(F)c1

Procedure:
5 a) 1 eq. of triethyl 2-phosphonopropionate was deprotonated at 0° C. with 1 eq. of n-butyllithium in hexane and then treated at RT with 1 eq. of 3,5-difluorobenzaldehyde. After the aldehyde had completely reacted, the mixture was worked up with water and extracted three times by shaking with toluene. After the combined organic phases had been dried over magnesium sulfate, the solvent was removed under vacuum and the residual crude product was separated by chromatography on silica gel using EE/HEP mixtures as the eluent. Ethyl E-3-(3,5-difluorophenyl)-2-methylacrylate was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccn1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccn1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
Methyl 1-(4-chlorobenzyl)-1H-pyrrole-2-carboxylate (550 mg, 2.203 mmol) was dissolved in ethanol (10 mL) and 7M aq. NaOH (8 mL). The reaction was stirred at 70° C. for 4 h and allowed to cool for 1 h. The ethanol was stripped by rotary evaporation until material began to precipitate, at which point the aqueous mixture was cooled in an ice bath and acidified with conc. HCl, which elicited further precipitation. The precipitate was collected over a filter and washed with a small amount of cold 1M HCl and dried under high vacuum to provide 375 mg of the title compound as a white, powdery solid.
Reaction SMILES: C([O:8][C:9](=[O:27])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:26])[C@H:16]([CH3:25])[NH:17][C:18](=[O:24])[C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)C1C=CC=CC=1.C(O)C.[H][H]>>[NH:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:27])=[O:8])=[O:26])[CH3:25])=[O:24]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CCO
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Into a Parr flask flushed with argon containing 450 mg of 10% palladium on charcoal catalyst was added a solution of Ac-L-prolyl-L-alanyl-L-proline benzyl ester in (1.0 g, 2.41 mmol) absolute ethanol (100 ml). The contents were shaken under 40 psi of hydrogen overnight at room temperature. The mixture was filtered through celite and the filtrate concentrated on a rotary evaporator to give crude Ac-L-prolyl-L-alanyl-L-proline which was crystallizedfrom tetrahydrofuran-methanol-ether to give the desired product (0.57 g) in 73% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Cl)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13]([O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1Cl
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
A mixture of 3-(benzyloxy)-5-chloro-2-nitropyridine (1.00 g, 3.78 mmol), potassium carbonate (2.09 g, 15.1 mmol), 2-chlorophenol (1.46 g, 11.3 mmol) and DMF (16 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled, partitioned between a 1:1 mixture of ethyl acetate (60 mL) and ether and water (60 mL). The organic layer was washed with 2N NaOH (30 mL), water, and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 5:1 hexane:ethyl acetate to afford 3-(benzyloxy)-5-(2-chlorophenoxy)-2-nitropyridine (0.73 g, 54.2% yield) as a light yellow solid. 1H NMR (CDCl3) δ 5.16 (s, 2H), 6.90 (s, 1H), 7.09 (d, 1H), 7.28-7.37 (m, 7H), 7.52 (d, 1H), 7.72 (s, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH:5]1[CH3:19])([CH3:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH3:49])[C:38]=1[C:39]([NH2:41])=[O:40]>CC(N(C)C)=O.O>[CH:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:41][C:39](=[O:40])[C:38]4[C:37](=[CH:45][C:44]([O:46][CH3:47])=[CH:43][C:42]=4[O:48][CH3:49])[N:36]=3)=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[CH3:19])([CH3:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(C)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)C)[C@@H](C)C4)cc3)nc2c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 4-(4-isopropyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.400 g, 1.50 mmol), NaHSO3 (0.195 g, 1.80 mmol), and p-TsOH (0.030 g, 0.15 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.400 g, 2.40 mmol) in DMA (10 mL). The reaction was stirred at 140° C. for 4 hours, then at room temperature overnight. The mixture was diluted with H2O and extracted with CH2Cl2. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, followed by reverse-phase chromatography, eluting with 10% to 90% CH3CN in H2O, afforded the title compound (0.114 g, 17%). 1H NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H), 8.09 (d, J=8.9 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.66 (s, 1H), 6.44 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.41-3.44 (m, 2H), 3.11-3.23 (m, 5H), 1.00-1.03 (m, 12H). ESI MS m/z 437 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]1[CH:82]=[CH:81][C:61]([C:62]([O:64][C:65]2[CH:66]=[N:67][C:68]([CH2:71][NH:72][CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[CH:69][CH:70]=2)=[O:63])=[CH:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56].C(N(CC)CC)C>CN(C=O)C>[CH2:50]([O:57][C:58]1[CH:82]=[CH:81][C:61]([C:62]([O:64][C:65]2[CH:66]=[N:67][C:68]([CH2:71][N:72]([CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:22]([F:25])([F:24])[F:23])=[CH:21][CH:20]=3)=[CH:69][CH:70]=2)=[O:63])=[CH:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNCC(=O)OC(C)(C)C)nc2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (40 mg, 0.11 mmol) in DMF (1 mL) was added HATU (45 mg, 0.11 mmol). After stirring for 1 h at room temperature, 6-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)pyridin-3-yl 4-(heptyloxy)benzoate INT-20 (61.7 mg, 0.13 mmol) was added followed by triethylamine (22.8 mg, 0.22 mmol). The reaction mixture was allowed to stir at room temperature for overnight. The final product was isolated by HPLC purification to give 6-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)pyridin-3-yl 4-(heptyloxy)benzoate INT-21. LCMS-ESI (m/z) calculated for C43H48F3N3O8: 792; no m/z observed, tR=4.83 min (Method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:21]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)[N:22]=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)CC(=O)c1ccnc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(-c2ccnc(Cl)c2)n(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A mixture of 1-(2-chloro-4-pyridinyl)-1,3-butanedione (from step 2, Example 29) (2.5 g, 12.69 mmol), p-chlorophenylhydrazine·HCl (2.7 g, 15.11 mmol) and triethylamine (2.1 mL, 15.11 mmol) in ethanol (50 mL) was heated to reflux overnight (about eighteen hours). The resulting dark colored solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to give 2-chloro-4-[1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine as an orange colored solid (1.5 g, 39%). MP: 110.05° C. This product was used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]CC3C=CC=CC=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[C:15]1([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1
Reactant: c1ccc(COc2cccc(-c3cccc(OCc4ccccc4)c3)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1cccc(-c2cccc(O)c2)c1

Procedure:
146 g (0.392 mol) of 3,3′-dibenzyloxybiphenyl are dissolved in 1.5 I of THF and hydrogenated to completion on a Pd/C catalyst. The catalyst is filtered off, the filtrate is evaporated, and the residue is filtered through silica gel with toluene/ethyl acetate, giving biphenyl-3,3′-diol as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][N:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6].[Br:19]Br>C(Cl)Cl>[NH2:1][C:2]1[C:16]([Br:19])=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][N:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6]
Reactant: BrBr
Reactant: COc1ccc(N)c(CN(C)C2CCCCC2)c1
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN(C)C2CCCCC2)c1

Procedure:
2-Amino-3-bromo-N-cyclohexyl-5-methoxy-N-methyl-benzylamine was prepared from 2-amino-N-cyclohexyl-5-methoxy-N-methyl-benzylamine and bromine analogous to Example 9. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride): 3240 cm-1NH2 ; 3410 cm-1NH2 ; 2860 cm-1 aliphatic hydrocarbon; 2940 cm-1 aliphatic hydrocarbon; 2830 cm-1OCH3 ; 2800 cm-1N-alkyl; 1480 cm-1C=C; 1590 cm-1C=C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7])#[N:2].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([O:15][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C#N)c2)cc1
Product: CCOC(=O)COc1ccc(NC(=O)c2cccc(C#N)c2)c(NC(=O)c2ccc(C(C)C)cc2)c1

Procedure:
Using a procedure similar to Example 2A except starting with N1-(3-cyanobenzoyl)-N2-(4-isopropylbenzoyl)-4-hydroxy-1,2-benzenediamine and ethyl bromoacetate, the title compound was obtained as a solid (78%); IR(CHCl3): 2966, 1757, 1655, 1610, 1514 cm−1; NMR(300 MHz, CDCl3): δ1.31 (m, 9H), 3.00 (m, 1H), 4.24 (t, 2H, J=6.9 Hz), 4.35 (s, 2H), 6.59 (d, 1H, J=9.0 Hz), 6.95 (s, 1H), 7.35 (m, 3H), 7.64 (m, 1H), 7.82 (d, 1H, J=7.5 Hz), 7.92 (d, 2H, J=8.1 Hz), 8.23 (d, 1H, J=7.5 Hz), 8.32 (s, 1H), 9.06 (br s, 1H), 9.61 (br s, 1H); MS(FD): 485.2.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH:17]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:18][N:19]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH3:20]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([N:19]([CH2:18][CH:17]([OH:16])[CH2:28][N:29]([CH3:31])[CH3:30])[CH3:20])=[CH:22][CH:23]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(O)CN(C)c1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Product: CN(C)CC(O)CN(C)c1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 1, but starting from 4-anilino-5-bromo-2-chloropyrimidine (Method 13) and 4-{N-[2-hydroxy-3-(N,N-dimethylamino)propyl]-N-methylamino}aniline (Method 116), the product was obtained. MS (MH+): 471, 473; HPLC (RT): 4.53.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:13]=[CH:14][CH3:15])([CH3:12])([CH3:11])[CH3:10].[ClH:16]>O1CCCC1.C([Li])CCC.C(OCC)(=O)C>[ClH:16].[ClH:16].[C:9]([NH:13][CH:14]([CH3:15])[CH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccc(O)cn1
Reactant: CC=NC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(O)cn1)NC(C)(C)C

Procedure:
To the suspension of 9.8 g of 2-methyl-5-pyridinol in 200 ml of tetrahydrofuran, 135 ml of 1.6 molar n-butyllithium are added during 30 minutes while stirring under nitrogen at -20°. After 3 hours 10 g of t-butyliminoethane are added during 30 minutes at said temperature and the resulting mixture is processed as described in Example 4, except that the final solution is acidified with hydrogen chloride in ethyl acetate, to yield the 2-(2-t-butylaminopropyl)-5-pyridinol dihydrochloride melting at 218°-220°.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=2)[C:9]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8]1.[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28]>C1(C)C=CC=CC=1>[C:20]1([CH2:19][CH2:18][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:17]=[N:26][NH:27][N:28]=4)[CH:11]=3)[NH:7][N:8]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2c(c1)c(CCc1ccccc1)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: c1ccc(CCc2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1
Yield: 37 %

Procedure:
The title compound was prepared as described in Example 167, using 1-perhydro-2H-pyran-2-yl-3-(2-phenylethyl)-1H-indazole-5-carbonitrile (0.117 g, 0.35 mmol), azidotributyl tin (0.353 g, 0.292 mL, 1.06 mmol) in toluene (5 mL). After hydrolysis of the protecting group under acidic conditions, the compound was purified by acid/base extraction. The residue was partitioned between 6.0N NaOH and ethyl acetate. The aqueous phase was then acidified with 6.0 N aqueous hydrogen chloride, to pH 3–4, resulting in the formation of a white precipitate that was collected by filtration, washed with small portions of cold water and dried under vacuum (0.038 g, 37% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.05 (br s, 1H), 8.5 (s, 1H), 8.0 (d, 1H), 7.65 (d, 1H), 7.3 (m, 4H), 7.15 (m, 1H), 3.3 (m, 2H), 3.1 (m, 2H); ES-MS (m/z) 291 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:29][CH2:28][N:27]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1)C3
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(S(C)(=O)=O)CC1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a solution of Example 3 (100 mg; 0.23 mmol; 1 eq.) and TEA (82 μL; 0.59 mmol; 2.5 eq.) in DCM (3 mL) at 0° C. was added methanesulfonyl chloride (22 μL; 0.28 mmol; 1.2 eq.). The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed successively with 0.1M HCl and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (42 mg, 35%) as a white solid. 1H NMR (CDCl3) δ 7.43-7.34 (m, 2H), 7.12-7.05 (m, 1H), 7.01-6.96 (m, 1H), 4.98 (s, 0.7H), 4.97 (s, 1.3H), 4.69-4.64 (m, 3H), 3.39-3.32 (m, 2H), 3.18-3.08 (m, 2H), 2.91 (s, 2H), 2.86 (s, 1H), 2.72 (s, 3H), 2.70 (s, 1H), 2.62 (s, 2H), 2.00-1.93 (m, 4H). HPLC (max plot) 98.0%, Rt 3.61 min. UPLC/MS: (MS+) 504.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=O)[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[N:22][OH:23])[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCOc1cccc2c1C(=O)CO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COCCOc1cccc2c1C(=NO)CO2
Temperature: 23 °C
Yield: 72.2 %

Procedure:
A mixture of the above described 4-(2-methoxy-ethoxy)-benzofuran-3-one (1.9 g, 9 mmol), sodium acetate (1.5 g, 19 mmol) and hydroxylamine hydrochloride (1.3 g, 19 mmol) in ethanol (15 mL) was refluxed for 4 h. Cooled to 23° C., filtered the precipitate off, washed with water and ethanol and dried in high vacuum to give the title compound as a white solid (1.45 g, 71%); MS: m/e=224.1 (M+H−).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.[NH3:31]>CN(C=O)C>[F:30][C:2]([F:1])([F:29])[CH2:3][N:4]=[C:5]([NH2:31])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CN(C)C=O
Product: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-[(3-phthalimido)propylthio]pyrimidine (0.4 g.), N,N,-dimethylformamide (5 ml.), saturated ethanolic ammonia (10 ml.) and yellow mercuric oxide (280 mg.) was stirred at room temperature for 3 hours and then filtered and the filtrate evaporated to dryness. A solution of the residue in ethanol (10 ml.) was treated with hydrazine hydrate (1 ml.), the mixture heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with 1N hydrochloric acid and then filtered and the filtrate basified with 17N NaOH. The mixture was extracted with ether and the combined ether extracts dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(3-amino)propylthio]pyrimidine which was used without further purification.