Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.[CH3:14]I>C1COCC1>[CH3:14][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: CI
Reactant: Oc1cccc2cccnc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc2cccnc12
Yield: 102.4 %

Procedure:
Add potassium hydroxide (435 g, 7.76 mol) to a solution of 8-hydroxy quinoline (250 g, 1.724 mol) in THF (10 L) at ambient temperature and stir. Add methyl iodide (435 g, 2.58 mol) dropwise and stir overnight. Filter the reaction mixture and wash the solid with THF (2 L). Concentrate the solution to dryness; add water; extract with dichloromethane (2×3 L); combine the organic layers; and wash with brine. Collect the organic layers and dry over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give a red oil, which solidifies on standing, to give the title compound (281 g, 102%), which can be used without further purification. ESI (m/z) 160(M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]=[N+:19]=[N-:20])=[C:11]([O:21][CH3:22])[CH:10]=1)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[N:18]([CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[CH:10][C:11]=1[O:21][CH3:22])=[N+:19]=[N-:20]
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCCN=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CN)ccc1OCCN=[N+]=[N-]
Temperature: 100 °C
Yield: 100 %

Procedure:
A solution of 32 (0.103 g, 0.32 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid and heated at 100° C. for 1 hr. The reaction mixture was concentrated in vacuo. The residue was diluted with toluene and concentrated in vacuo several times to give 33 as brown solid (0.115 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[N:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C(O)(=[O:19])C.C([O-])(=O)C.[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:19])[N:5]=[N:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1Cl
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccccc1Oc1nnc(O)cc1Cl
Yield: 85.9 %

Procedure:
A mixture comprising 578 mg (2.27 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2), acetic acid (10 mL) and 0.45 g (4.6 mmol) of potassium acetate was refluxed for 5 hours. The reaction mixture was allowed to stand for cooling, and after adding 50 mL of water, the mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed to obtain 461 mg (1.95 mmol, Yield: 85.9%) of 5-chloro-6-(2-methylphenoxy)-3-pyridazinol.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:44][CH:45]1[CH2:50][CH2:49][O:48][C:46]1=[O:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:44][CH:45]3[CH2:50][CH2:49][O:48][C:46]3=[O:47])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCOC1=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Agent: Br
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)NC3CCOC3=O)cc2)cc1

Procedure:
The product from Example 234B and alpha-amino-gamma-butyrolactone hydrobromide were processed as described in Example 251A to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ8.94 (s, 1 H), 8.33 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.53 (dd, 1 H), 4.34 (t, 1 H), 4.20 (m, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (t, 2 H), 3.44 (m, 1 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.16 (m, 3 H), 1.55-1.78 (m, 4 H); MS (ESI+) m/z 672 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[N:9]2[CH:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=3[N+:31]([O-])=O)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[Sn](Cl)Cl>CCO>[NH2:31][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:23]=1[NH:22][CH:19]1[CH2:20][CH2:21][CH:16]([N:9]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]([CH3:13])([CH3:14])[O:11][C:10]2=[O:15])[CH2:17][CH2:18]1)[C:27]#[N:28]
Reactant: CC1(C)OC(=O)N(C2CCC(Nc3ccc(C#N)cc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccc(C#N)cc3N)CC2)[C@H]1c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a flask charged with (S)-4-((4-(4-(4-fluorophenyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)cyclohexyl)amino)-3-nitrobenzonitrile (0.490 g, 1.083 mmol) was added EtOH (4.33 mL) followed by tin (II) chloride (0.616 g, 3.25 mmol). The resulting yellow suspension was heated overnight at 80° C. LC-MS analysis of the resulting suspension indicated about 90% conversion to the desired product (215 nm). Additional EtOH (4 mL) was added to aid solubilization and additional SnCl2 was added (300 mg). The resulting mixture was heated at 80° C. After 1 hour, LC-MS indicated complete conversion. The yellow suspension was dried under reduced pressure and the residue was purified with a 50 g SNAP column ramping DCM:MeOH (90:10) in DCM (0-30%, then isocratic at 30%, detection at 215 nm) to provide (S)-3-amino-4-((4-(4-(4-fluorophenyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)cyclohexyl)amino)benzonitrile (0.156 g, 0.369 mmol, 34.1% yield) as a brown oil and as a mixture of isomers with impurities present (˜20% based on LC-MS). The material was used in the next step without further purification. m/z (ESI) 423.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.[NH2:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11]>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([NH:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11])=[O:8]
Reactant: O=C(O)C1CCCO1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)C2CCCO2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using tetrahydro-2-furoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was:408 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18]CC)=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[ClH:21]>>[ClH:21].[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Br)c1
Agent: Cl
Product: O=C(O)C=Cc1ccc(Cn2ccnc2)c(Br)c1

Procedure:
A mixture of ethyl 3-[3-bromo-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate (0.12 g) in hydrochloric acid (2 ml, 6M) was stirred and heated under reflux for 2 h. The reaction mixture was concentrated under reduced pressure and toluene (5 ml) was added and the reaction mixture was again concentrated to give a white solid. Recrystallisation of the solid from ethanol/ether gave 3-[3-bromo-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoic acid hydrochloride as a white solid, m.p. 247°-249°.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([OH:5])=[O:4].[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16]>C(Cl)Cl>[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[NH2:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)O
Reaction time: 6 h

Procedure:
To a solution of t-BOC-Gly-Ama-diEt (985.2 g, 2.96 mol) in 770 mL CH2Cl2, 770 mL trifluoroacetic acid (TFA) was added. The resulting mixture was stirred and after 6 hour a precipitate formed, which was collected after 8 hours. Recrystallization from CHCl3 gave 1025.1 g of TFA-Gly-Ama-diEt as a white solid: 1H NMR (DMSO-d6): δ 9.34 (d, 1H, NH), 8.13 (b.s., 3H, NH2 TFA salt), 5.17 (d, 1H, CH), 4.20 (m, 4H, CH2), 3.71 (d, 2H, CH2), 1.22 (t, 6H, CH3).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N:20]=[C:21]=[O:22].CCCCCC>ClCCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[NH:20][C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:22]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(I)cc1
Solvent: CCCCCC
Solvent: ClCCCl
Product: O=C(Nc1ccc(I)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 0 °C
Yield: 81.6 %

Procedure:
To a solution of 4-iodoaniline (438 mg, 2.0 mmol) in 15.0 mL 1,2-dichloroethane at rt was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.304 mL, 2.1 mmol). After 50 minutes 3 mL hexane was added, the mixture cooled to 0° C., the precipitant filtered and rinsed with 10% EtOAc/hexane to give the title compound as a light purple solid (692 mg, 82%). 1H NMR (DSMO-d6) δ: 9.26 (s, 1H), 8.90 (d, J=2.9 Hz, 1H), 8.59 (dd, J=7.3, 2.3 Hz, 1H), 7.60-7.65 (m, 2H), 7.46-7.54 (m, 1H), 7.36-7.43 (m, 1H), 7.29-7.34 (m, 2H).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH3:55][N:56]([CH3:61])[CH2:57][C:58](O)=[O:59].C(O)C(N)(CO)CO>>[CH3:55][N:56]([CH3:61])[CH2:57][C:58]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:15]=2)[CH2:20]1)=[O:59]
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
2-Dimethylamino-1-[7-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), PS-DCC (800 mg, 1.1 mmol), HOBt (80 mg, 0.77 mmol), NEt3 (0.21 mL, 1.5 mmol) and N,N-dimethylglycine (1.1 mL, 15 mmol) via a procedure substantially analogous to Procedure E except that PS-trisamine resin beads (700 mg, 2.6 mmol) is used in the work up to scavenge the excess HOBt and N,N-dimethylglycine. The free base product (35 mg, 19% yld) is isolated as an oil. MS(ES+)360.5(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:5]=21.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([NH:29][C:30](=[O:32])[CH3:31])=[CH:26][CH:27]=[CH:28][C:5]=21
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(N)cccc32)cc(Br)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(NC(C)=O)cccc32)cc(Br)c1OC
Temperature: 0 °C
Yield: 93.1 %

Procedure:
2,7-Diamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (10) (45 mg, 0.1 mmol) was taken in pyridine (2 ml) at 0° C., charged with acetic anhydride (11 mg, 0.11 mmol) and stirred further at 0° C. under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (46 mg, 93%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[I:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([C:20](=[CH:23]NC1C=CC=CC=1)[C:21]#[N:22])=[O:19]>C(O)C.CO>[NH2:22][C:21]1[N:2]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[CH3:13])[C:7]([OH:9])=[O:8])[N:3]=[CH:23][C:20]=1[C:18](=[O:19])[C:17]1[CH:31]=[CH:32][CH:33]=[C:15]([I:14])[CH:16]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Reactant: Cc1ccc(C(=O)O)cc1NN
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Temperature: 75 °C
Yield: 22 %

Procedure:
To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 1 (Example 3A, 314 mg, 1.54 mmol, 1.0 eq) in 50 mL of ethanol and 5 mL of methanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2 (579 mg, 1.54 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84). The mixture was heated to 75° C. for 18 h. The precipitated solids were collected on a fritted filter and were washed with ethanol to provide 3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid 3 (153 mg, 22%) as a white solid. MS m/z 448 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ2.18 (s, 3H), 7.05 (bs, 2H), 7.34 (dd, J1=J2=7.7 Hz), 7.58 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.81 (m, 2H), 7.94 (m, 1H), 7.98 (m, 1H), 8.03 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO>CCO>[C:5]1([CH:4]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:3]([O:2][CH3:1])=[O:27])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CO
Solvent: CCO
Product: COC(=O)C(c1ccccc1)C1CCNCC1
Yield: 99 %

Procedure:
Following the same procedure as described in Example 10, step 1, but substituting 2-nitro-4-(thiophen-2-yl)aniline for compound 91, and MeOH for EtOH, the title compound 92 (0.384 g, 99%) was obtained as a colorless oil. LRMS (ESI): (calc) 233.31 (found) 234.14 (MH)+
Reaction SMILES: [CH2:1]1[O:15][C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH:13]=C)([OH:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+].C[OH:19]>>[CH2:1]1[O:15][C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH2:13][OH:19])([OH:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C=CCCC1(O)CCC2(CC1)OCCO2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: OCCCC1(O)CCC2(CC1)OCCO2

Procedure:
A mixture of 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethylene ketal (1.8 g) in methanol (40 mL) was ozonized at -70° C. until a persistant blue color was obtained. The ozonide was decomposed with excess sodium borohydride at -60° C. The reaction was concentrated in vacuo and the residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted several more times with ethyl acetate and the combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography with ethyl acetate as the eluent to afford 4-(3-Hydroxypropyl)-4-hydroxycyclohexanone ethylene ketal as an oil.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[C:16]([OH:17])=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:17][C:16]1[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: Cc1ccc(-c2nc3ncccc3cc2O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccc(C)cc3)c2cc1OC
Temperature: 130 °C
Reaction time: 14.5 h
Yield: 19.5 %

Procedure:
2-p-Toluyl-[1,8]naphthyridin-3-ol (2 mg), 4-chloro-6,7-dimethoxyquinoline (6 mg), and 4-dimethylaminopyridine (3 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 130° C. for 14.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (0.7 mg, yield 20%).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11](=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14]>O>[CH:11](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14]
Reactant: NNC(=O)c1ccccc1
Reactant: O=Cc1ccccc1O
Solvent: O
Product: O=C(NN=Cc1ccccc1O)c1ccccc1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A reaction vessel was charged with 13.6 g (0.10 mole) of benzhydrazide and 50 ml of water, and the vessel contents were agitated as 13.4 g (0.11 mole) of salicylaldehyde was added. Heat was evolved and the mixture was stirred at room temperature for an additional hour, then warmed briefly on a steam bath. The precipitate which had formed was filtered off, washed with water and ether, and dried under vacuum. It was then placed in 300 ml of ethanol for several hours and the remaining solid, crystalline in appearance, was filtered off and dried under vacuum. The filtrate was then diluted with water and cooled, forming additional precipitate which was then filtered off and dried. Both precipitates were combined to yield 19.0 g (79% of theoretical yield) of salicylidene benzhydrazide, with a melting point range of 172°-174° C.
Reaction SMILES: [N+](C1C=CC(C([NH:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=O)=CC=1)([O-])=O.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(NCCN1CCc2ccccc2C1)c1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCCN2CCc3ccccc3C2)cc1

Procedure:
The title compound was prepared by Method A using 2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinoline (described in Example 174) and 4-nitrobenzenesulfonyl chloride to produce the desired product in 98% yield. This material was crystallized from EtOAc to afford a gold-colored solid; mp 142.5°-144.5° C.; IR (KBr) 3372, 3110, 2778, 1929, 1603, 1521, 1305, 1151, 969 and 739 cm-.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:3]2([CH2:8][CH2:7][CH:6]([CH:9]=[C:10](Br)Br)[CH2:5][CH2:4]2)[O:2]1.C([Li])CCC>O1CCCC1.CCCCCC>[C:9]([CH:6]1[CH2:5][CH2:4][C:3]2([O:2][CH2:1][CH2:14][O:13]2)[CH2:8][CH2:7]1)#[CH:10]
Reactant: BrC(Br)=CC1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CC1CCC2(CC1)OCCO2
Temperature: 20 °C
Yield: 91.1 %

Procedure:
A solution of 14 g of 1,1-ethylenedioxy-4-(2,2-dibromovinyl)cyclohexane in 70 ml of tetrahydrofuran was cooled to -20° C. and treated slowly at this temperature with 76.62 ml of a 1.4M solution of butyl lithium in hexane (exothermic reaction). The cooling bath was removed and the mixture was left to warm to 20° C. within about 20 minutes. The mixture was subsequently treated with 150 ml of water and extracted three times with diethyl ether. The organic phases were washed twice with water and the wash-water was back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate, filtered and evaporated. Low-pressure chromatography of the resulting, yellow liquid (8 g) on silica gel with ethyl acetate/petroleum ether (vol. 7:93) gave 6.5 g (91%) of 4-ethynyl-1,1-ethylenedioxycyclohexane as a clear liquid.
Reaction SMILES: [F:1][C:2]([F:26])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[OH-:27].[K+]>C(#N)C.O.O1CCOCC1>[F:26][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH:25]=[O:27])=[CH:23][CH:24]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: [OH-]
Reactant: Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Yield: 30.7 %

Procedure:
The product from Step 1 (7.0 g, 18.7 mmol) was dissolved in acetonitrile (200 mL) and stirred at ambient temperature while ceric ammonium nitrate (32 g, 58 mmol) in H2O (60 mL) was added in portions over 10 min. The solution was then heated to reflux for 4 h, cooled, and diluted with H2O (200 mL). The solution was extracted with ether (2×200 mL), and the combined organic layer was dried and concentrated to give an orange oil. This material was dissolved in dioxane (40 mL) and treated with a solution of potassium hydroxide (KOH; 5 g, 90 mmol) in H2O (20 mL). The solution was heated to reflux for 2 h, then cooled and diluted with H2O (100 mL). The aldehyde precipitated and was collected by filtration. Recrystallization from MeOH/H2O gave the pure aldehyde as a white solid (2.2 g, 30%): mp 137-144° C.; 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.65 (s, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H); ESIMS m/z 384.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O>[Pd].C(OCC)(=O)C>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(N)c1
Yield: 100000 %

Procedure:
A mixture comprising 4-amino-3-nitrobenzonitrile (5 g, 0.031 mmol) and palladium on carbon (500 mg, 10 wt %) and ethyl acetate (150 mL) in a Parr flask was hydrogenated for 60 minutes (45-50 psi), filtered over celite and concentrated to dryness to provide 3,4-diaminobenzonitrile (4.09 g, 0.031 mol) as a white solid; PB-CI/MS: 134=(MH+); 1H-NMR (300 Mhz, DMSO-d6): 4.81 (bs, 2H), 5.39 (bs, 2H), 6.494 (d, 1H), 6.703 (s, 1H), 6.723 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@@H:20]3[CH2:24][NH:23][CH2:22][C@@H:21]3[C:25]([O:27][CH3:28])=[O:26])=[O:18])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH:40](=O)[CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.C(OCC)(=O)C>[CH2:40]([N:23]1[CH2:24][C@@H:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:30][CH:29]=2)[C@@H:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:22]1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)C=O
Reactant: COC(=O)[C@H]1CNC[C@H]1NC(=O)c1ccc(Cc2cc(C)nc3ccccc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(CC(C)C)C[C@H]1NC(=O)c1ccc(Cc2cc(C)nc3ccccc23)cc1
Yield: 79.1 %

Procedure:
The TFA salt (403a) (70 mg, 0.11 mmol) was dissolved in 1 mL of dichloromethane. Diisopropylethylamine (43 mg, 60 μL, 0.33 mmol), isobutyraldehyde (12 mg, 5 μL) and NaBH(OAc)3 (35 mg, 0.17 mmol) were added. The whole mixture was stirred until the reaction went to completion. The solution was diluted with ethyl acetate and washed with saturated NaHCO3, H2O and brine. The organic layer was dried over MgSO4. After filtration and concentration, the residue was purified on silica gel to provide methyl (3S,4S)-1-isobutyl-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxylate (40 mg, 78%). MS (ES+): 460 (M+1).