Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:15]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1)[NH2:16]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[C:4](=[O:14])[N:15]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[CH:19][N:18]=3)[NH:16][CH:6]=2)[CH:9]=1
Reactant: CCOC(=O)C(=CO)c1cccnc1
Reactant: NNc1cc(C(F)(F)F)ccn1
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(C(F)(F)F)ccn1

Procedure:
The compound is prepared analogously to Example 2 from 18 mg (0.09 mmol) of the compound from Example 2A and 18 mg (0.10 mmol) 2-hydrazino-4-(trifluoromethyl)pyridine [R. A. Evans, C. Wentrup, J. Chem. Soc. Chem. Commun. 15, 1062-1064 (1992)]. 11.7 mg (41% of th.) of the title compound are obtained as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:20][C:21]2[N:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=[O:3])[CH3:2].Cl.CO>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][N:26]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl
Solvent: CO
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCNCC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
A mixture of 339d (130 mg, 0.18 mmol) and HCl/methanol (4.0 mL) was stirred at room temperature for 4 h. It was then concentrated under reduced pressure to afford crude 339e (100 mg, 87%), which was used in the next step without further purification. MS-ESI: [M+H]+ 637.3.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=O.C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([O:30][CH3:31])[C:22]=3[O:21][CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 1.27 g of the compound (9) synthesized in Example 2 and 0.8 g of 2,3,4-trimethoxybenzaldehyde was stirred at 120° C., then, 0.18 ml of formic acid was added dropwise. This was stirred for one hour at the same temperature, then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added and the results were shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the above-referenced compound (29) in an amount of 1.46 g (yield 73%).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])(OCC)=O>>[C:30]1(=[O:39])[N:1]([C@@H:2]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: COC(=O)C[C@@H](N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@H](c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O

Procedure:
Methyl (3R)-3-amino-3-(3,4-dimethoxyphenyl)propionate (0.25 g, 0.91 mmol), sodium carbonate (0.10 g, 0.91 mmol) and N-carboethoxyphthalimide (0.20 g, 0.91 mmol) were allowed to react according to the procedure of Example 85. Methyl (3R)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionate was obtained as a white powder, 0.29 g (88%); 1H NMR (DMSO-d6, 250 MHz) δ7.87 (br s, 4H, Ar), 6.80-7.10 (m, 3H, Ar), 5.64 (dd, 1H, J1=7 Hz, J2=9 Hz), 3.73 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 355 (s, 3H, OCH3), 3.30-3.67 (m, 2H); 13C NMR (DMSO-d6) δ170.8, 167.6, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.2, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal. Calcd for C20H19NO60.80 H2O. Theoretical C, 62.60; H, 4.99; N, 3.69. Found C, 62.60; H, 4.93; N, 3.69. HPLC 99.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:32])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1ccccc1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-phenyl-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 5 days under reflux conditions to give the title compound as yellow oil. MS: m/e=445.1 [M+H+].
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:12][OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N([Cl:23])C(=O)C1>CN(C=O)C>[OH:13]/[N:12]=[C:11](\[Cl:23])/[C:9]1[CH:8]=[CH:7][C:6]2[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OB(O)c2ccc(C=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Temperature: 45 °C
Reaction time: 3 h
Yield: 105.5 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (1.38 g, 6.73 mmol) in DMF (15 mL) at rt was added NCS (1.07 g, 8.03 mmol). The reaction mixture was warmed to 45° C., stirred for 3 h and cooled to rt. The mixture was poured into ice-water (20 mL) and extracted with EA (20 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (1.7 g; 100% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=1[N+:15]([O-])=O)[CH3:2].[H][H]>CCO>[CH2:1]([O:3][C:4]([C:5]1[NH:15][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([C:13]#[N:14])[CH:9]=2)=[O:19])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Yield: 65.3 %

Procedure:
Add to 1.5 g of 3-(4-cyano-2-nitrophenyl)-2-oxopropionic acid ethyl ester, in EtOH (40 mL) 10% Pd/C (0.45 g) and stir under a hydrogen atmosphere until the theoretical amount of hydrogen is absorbed. Filter the mixture and concentrate the filtrate to afford 1.1 g of crude product. Purify by chromatography on SiO2 and elute with CH2Cl2. Concentrate the desired fractions and vacuum dry the residue over night (40° C.) to afford the title compound (0.8 g) as white crystals, mp 176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCNCCc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a mixture of 2-(4-chlorophenyl)ethylamine (1.56 g, 10 mmol) and potassium carbonate (2.8 g, 20 mmol) in CH3CN (50 ml) was added N-(3-bromopropyl)phthalimide (3.0 g, 11 mmol). The mixture was refluxed under stirring for 16 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2.5% methanol/chloroform) to afford N-[3-[2-(4-chlorophenyl)ethylamino]propyl]phthalimide (2.28 g, 67%): MS(FD) m/e 343 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 2H), 7.71 (m, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 3.74 (d, J=6.8 Hz, 2H), 2.82 (t, J=6.8 Hz, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 1.84 (m, 2H).
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1)C.[NH:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][N:17]=1)[NH2:15]>CO>[N:15](=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5]1)[N:14]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1
Reactant: NNC1=NCCc2ccccc21
Reactant: CCOC1=NCCc2ccccc21
Solvent: CO
Product: c1ccc2c(c1)CCNC2=NN=C1NCCc2ccccc21

Procedure:
A solution of 1-ethoxy-3,4-dihydroisoquinoline (4.25 g.) and 1-hydrazino-3,4-dihydroisoquinoline (3.9 g.) in methanol (40 ml.) was stirred at room temperature overnight and then at reflux for a day. More 1-ethoxy-3,4-dihydroisoquinoline (1 g.) was added during the reflux period. The solution was stripped of methanol and the solid was recrystallized from 2-propanol, affording 1,1'-azinobis(1,2,3,4-tetrahydroisoquinoline) (II: Y=Y' =Z=Z' H) (first crop, 2.6 g., m.p. 178°-179° C.). In this example 1-hydrazino-3,4-dihydroisoquinoline hydrochloride can be used instead of 1-hydrazino-3,4-dihydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)=[O:3].O1CCOCC1.[ClH:23]>>[ClH:23].[NH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH:4]1[C:2]([NH2:1])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1COCCN1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl 3-(aminocarbonyl)morpholine-4-carboxylate (0.48 g, 2.085 mmol) was taken up in 4 M HCl in dioxane (5 mL, 10.00 mmol) and maintained at room temperature overnight. The solvent was removed in vacuo to afford the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]12([NH:18][S:19]([C:22]3[CH:33]=[C:26]4[C:27](OC(=O)[NH:31][C:25]4=[CH:24][CH:23]=3)=[O:28])(=[O:21])=[O:20])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:27](=[O:28])[C:26]2[C:25](=[CH:24][CH:23]=[C:22]([S:19](=[O:21])(=[O:20])[NH:18][C:8]34[CH2:17][CH:12]5[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]5)[CH2:9]3)[CH2:15]4)[CH:33]=2)[NH2:31])[CH2:4][CH2:3]1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)NC34CC5CC(CC(C5)C3)C4)cc2c(=O)o1
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2cc(S(=O)(=O)NC34CC5CC(CC(C5)C3)C4)ccc2N)CC1
Temperature: 25 °C

Procedure:
2.7 g of 1-methylpiperazine are added slowly to a suspension of 10.2 g of 5-[N-(1-adamantyl)-sulfamoyl]-isatoic anhydride in 250 ml of absolute toluene, at 100° with stirring. After the addition is ended, the mixture is stirred for a further 1 hour at 100° and is allowed to cool to room temperature, the precipitate is separated off by decanting and the crude product thus obtained is recrystallised from ethanol. 5-[N-(1-Adamantyl)-sulfamoyl]-anthranilic acid (4-methyl)-piperazide with a melting point of 214°-215° is obtained. (Melting point of the hydrochloride: 298°-300°).
Reaction SMILES: C[O-].[Na+].I.[CH2:5]([S:7][C:8](=[NH:10])[NH2:9])[CH3:6].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C>CCO>[NH2:19][C:18]1[C:15]([C:16]#[N:17])=[CH:14][N:9]=[C:8]([S:7][CH2:5][CH3:6])[N:10]=1
Reactant: CCOC=C(C#N)C#N
Reactant: CCSC(=N)N
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: CCSc1ncc(C#N)c(N)n1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
A suspension of NaOMe (2.7 g, 50 mmol) in EtOH (200 mL) is added to a mixture of S-ethylisothiourea hydroiodide (11.58 g, 50 mmol), ethoxymethylidenemalononitrile (6.1 g, 50 mmol) and ethanol (250 mL) at 25° C. The reaction mixture is refluxed under N2 for 2 h, and then the solution is concentrated on a hot plate until precipitation is observed. After cooling, the solid is collected by suction filtration and is stirred in water at 25° C. Filtration and vacuum oven drying affords 4-amino-5-cyano-2-ethylthiopyrimidine (4.02 g, 45%) as a brown solid. 1H NMR δ (DMSO) 8.45 (1H, s), 7.90 (2H, brs), 3.00 (2H, q, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[C:21]([C:24](Cl)=[O:25])[NH:22][N:23]=1>N1C=CC=CC=1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:24]([C:21]2[NH:22][N:23]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=3[Cl:11])[CH:20]=2)=[O:25])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Reactant: NCCc1ccc(O)cc1
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(O)cc1)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Yield: 70.6 %

Procedure:
In pyridine (6 ml), 4-(2-amino-ethyl)-phenol (72 mg) was dissolved, and 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid chloride (137 mg) was added thereto under an ice cooling while stirring. Thereafter, the mixture was stirred at a room temperature for 17 hours and then concentrated under a reduced pressure, and the concentrate was purified by silica gel column chromatography (5% methanol-chloroform) to give the title compound (132 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[C:22]([F:23])[CH:21]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)c(F)c1

Procedure:
The title compound, MS: m/e=330.4 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1 H-imidazol-4-ylethynyl)-pyridine and 3,4-difluorobenzene boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][C:9]3=[N:12][CH:13]=[CH:14][N:8]3[CH2:7][C:6]=2[CH:15]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][C:9]3=[N:12][CH:13]=[CH:14][N:8]3[CH2:7][C:6]=2[CH:15]=1
Reactant: Clc1ccc2c(c1)Cn1ccnc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1 mmol of 7-chloro-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and worked up to give the desired product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[O:4][N:3]=1.CCN(C(C)C)C(C)C.[C:21]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:35][CH2:34][CH:31]2[CH2:32][CH2:33][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:29][CH2:30]2)=[O:11])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)CCc1cc(O)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CCc2cc(O)no2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 3-(3-hydroxyisoxazol-5-yl)propanoic acid (300 mg, 1.909 mmol) in DMF (7 mL) was added DIPEA (0.667 mL, 3.82 mmol) followed by 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate (COMU) (981 mg, 2.291 mmol). The resulting brown solution was stirred at RT for 5 mins and then treated with 1-BOC-4-(aminomethyl)piperidine (409 mg, 1.909 mmol). After stirring at RT for 2 hrs, the solution was concentrated under reduced pressure and the residue suspended in 0.2M aqueous HCl (200 ml). The mixture was extracted with EtOAc (2×100 ml) and the combined extracts were dried (MgSO4) and concentrated under reduced pressure. The crude residue was dissolved in DCM (100 ml) and treated with 2M NaOH (50 ml). The mixture was stirred vigorously at ambient temperature for 16 hrs. The mixture was then acidified with citric acid and the organics removed, dried (MgSO4) and concentrated under reduced pressure. The residue was applied to a 24 g silica cartridge and eluted with 0-100% EtOAc/iso-hexane. The product fractions were combined and concentrated to give a tert-butyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate as a gum.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[N:6]2)[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnn(CC2CC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(CC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-4-nitro-1H-pyrazole (8.37 g, 50.1 mmol) in methanol (150 mL) was added 10% Pd/C (840.0 mg, 0.7893 mmol). The suspension was stirred at room temperature under a H2 atmosphere for 2 h. Filtered and the filter cake was washed with MeOH (50 mL×3). The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100 to 1/50) to give the title compound as purple oil (5.5 g, 80%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[C:14]([C:15]([O-:17])=[O:16])=[C:13]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])[N:12]=[N:11]2)=[CH:7][CH:6]=1.Cl>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])[N:12]=[N:11]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2nnc(C(=O)c3ccccc3[N+](=O)[O-])c2C(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(C(=O)c3ccccc3[N+](=O)[O-])c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1N aqueous sodium hydroxide solution (50 ml) was added to a solution of 1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate (b-1) (10.17 g, 24.8 mmole) in tetrahydrofuran (100 ml), which was stirred at room temperature for 2 hours. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate and washed with saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2,3-triazole-5-carboxylic acid (c-1': LP) as a colorless crystalline powder. The product was dissolved in methanol (80 ml), 10% palladium on carbon (800 mg) was added, and the mixture was stirred in the hydrogen atmosphere at room temperature for 10 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Precipitates were collected by filtration to give 4-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylic acid (c-1: LP) (6.62 g, 75.8% over two steps) as a yellow crystalline powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH2:31])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([C:35]1[C:36]([N:42]=[CH:43][N:44]([CH3:46])C)=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1)#N>>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:46]2[C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[N:37][C:36]=3[N:42]=[CH:43][N:44]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2N)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 21 %

Procedure:
The product of Example 64A was reacted with the product of Example 9B using the procedure of Example 13D substituting the product of Example 64A for the product of Example 13C and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title compound (27 mg, 21%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.48 (s, 9 H) 2.69 (s, 3 H) 7.00 (d, J=8.09 Hz, 1 H) 7.34 (m, 4 H) 7.54 (m, 3 H) 7.72 (m, 1 H) 7.81 (d, J=8.09 Hz, 1 H) 8.01 (s, 1 H) 8.07 (s, 1 H) 8.60 (s, 1 H) 8.82 (d, J=8.46 Hz, 1 H) 9.60 (s, 1 H) 10.22 (s, 1 H) 10.34 (s, 1 H); MS (ESI+) m/z 657, 659 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([N:19]=[N+]=[N-])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([NH2:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C.[BH4-].[Na+].Cl>O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([NH2:19])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([NH2:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1c(OCc2ccccc2)ccc2c1CCC(N)C2

Procedure:
A solution was prepared from 3.4 g. of dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthalenecarboxamide (from Example 4) and 100 ml. of isopropanol. The solution was cooled and 0.5 g. sodium borohydride added thereto in small portions. After the addition had been completed, the reaction mixture was heated to reflux temperature under a nitrogen blanket for about 18 hours. The reaction mixture was then cooled and the cooled mixture diluted with water. The aqueous mixture was made acidic by the addition of 1 N aqueous hydrochloric acid. The aqueous acidic layer was extracted with ether and the ether extract discarded. The aqueous acidic layer was made basic by the addition of 10% aqueous sodium hydroxide. The alkaline layer was extracted several times with equal volumes of a 3:1 chloroform/methanol solvent mixture. The organic extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent therefrom yielded a residue comprising dl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide. TLC indicated a single spot at the origin. An infrared spectrum of the solid indicated no absorption attributable to an azide group. The residue was dissolved in chloroform and the chloroform solution saturated with gaseous hydrogen chloride. The solvent was removed in vacuo and the residue dissolved in methanol. Ether was added to the point of incipient precipitation and the solution was cooled overnight. Forty-eight hundredths grams of tan crystals melting above 235° C. consisting of dl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride were recovered.