Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=[O:17])#[N:2].C([OH:23])C.[OH-].[K+]>O>[C:16]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:23])([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2ccc(C)c(C)c2)c1C#N
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-n2ncc(C(=O)O)c2C(N)=O)cc1C

Procedure:
A 2.5 g. portion of ethyl 5-cyano-1-(3,4-dimethylphenyl)-4-pyrazolecarboxylate was hydrolysed in 50 ml. of ethanol and 12 ml. of water with 1.3 g. of potassium hydroxide under reflux for 21/4 hours. The mixture was then cooled and poured into 300 ml. of water. The aqueous mixture was filtered, made acid with concentrated hydrochloric acid, and filtered. The solids were dried and recrystallized from ethanol/water to obtain 1.62 g. of the desired product, m.p. 231°-232.5°. Its elemental analysis was as follows:
Reaction SMILES: [CH3:1][N:2]([C@@:10]1([CH3:24])[CH2:14][C:13](=O)[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(O)C.C(N(CC)CC)C.O>O1CCCC1>[CH3:1][N:2]([C@@:10]1([CH3:24])[CH2:14][CH2:13][N:12]([C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(N(C)C(=O)OC(C)(C)C)CC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](c1ccccc1)N1CC[C@](C)(N(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.4 %

Procedure:
The above-mentioned tert-butyl methyl-{(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}carbamate (3.94 g, 11.9 mmol) was dissolved in tetrahydrofuran (120 ml), then with cooling with ice, borane/tetrahydrofuran complex (29.6 ml 35.6 mmol) was added, followed by stirring at room temperature for 17 hours. Ethanol (36 ml), triethylamine (12 ml) and water (12 ml) were added to the reaction liquid, followed by stirring in an oil bath at 80° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, partitioned with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1, v/v) to obtain tert-butyl methyl-{(3S)-3-methyl-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}carbamate (2.44 g, 65%) as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:18]([O-])=O)[C:9]2=[O:21])[CH2:4][O:3]1.CO>[Pd]>[NH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][N:8]([CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:22])([CH3:1])[O:6]1)[C:9]2=[O:21]
Reactant: CC1(C)OCC(Cn2ccc3c([N+](=O)[O-])cccc3c2=O)O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCC(Cn2ccc3c(N)cccc3c2=O)O1

Procedure:
2-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-5-nitroisoquinolin-1(2H)-one (7.3 g, 0.024 mol) was stirred with palladium 10% wt. on calcium carbonate (1 g, 0.005 mol) in methanol (100 mL, 2 mol) under hydrogen (balloon) over 1 h at room temperature. The catalyst was filtered, the filtrate was concentrated to dryness, purified via flash chromatography (120 g of silica gel, 0-10% MeOH/CH2Cl2) to give a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:3]=1.CCN(CC)CC.[NH2:30][OH:31].Cl>CCO>[OH:31][N:30]=[C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]=[C:2]2[I:1])[NH2:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C#N)ccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(N)=NO)ccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
To a suspension of 3-iodo-1-tosyl-1H-indole-5-carbonitrile (1 g, 2.37 mmol) in EtOH (10 mL) was added Et3N (1.65 mL, 11.87 mmol) followed by NH2OH.HCl (410 mg, 5.93 mmol) and the reaction was stirred for 48 h at RT. The solvent was removed in vacuo and the residue was treated with H2O (10 mL) and extracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was further triturated with n-pentane to give N′-hydroxy-3-iodo-1-tosyl-1H-indole-5-carboximidamide (950 mg, 88.7%) as an off brown solid. MS (ESI, pos. ion) m/z: 455.8; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.8 Hz, 1H), 7.84-7.73 (m, 4H), 7.68 (d, J=8.4 Hz, 1H), 7.63-7.61 (m, 1H), 7.31-7.24 (m, 1H), 4.92 (brs, 2H), 3.14-3.09 (m, 1H), 2.36 (s, 3H).
Reaction SMILES: [CH2:1]([S:7][CH2:8][CH2:9]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CSCCCl.C(SCC[S:25][C:26]#[N:27])CCCCC>>[CH2:1]([S:7][CH2:8][CH2:9][N:27]=[C:26]=[S:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSCCSC#N
Reactant: CCCCCCSCCCl
Agent: CSCCCl
Product: CCCCCCSCCN=C=S

Procedure:
Example 1 is repeated with the exception that n-C6H13SCH2CH2Cl is used as a reagent instead of CH3SCH2CH2Cl and the reaction is allowed to proceed for seventy-five minutes. The product is isolated by distillation at reduced pressure and analyzed by gas chromatography/mass spectrometry which shows that the product is 0.7 percent n-C6H13SCH2CH2SCN and 97.0 percent n-C6H13SCH2CH2NCS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH2:12][C:13](=[N:19]O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)C(C)C)(C)C.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[O:10][N:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CCOC(=O)C(N)=NO
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2-(4-fluorophenyl)acetyl chloride (0.518 mL; 3.78 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (15 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.315 g (33%) of ethyl 5-(4-fluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)NCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 653.3 %

Procedure:
t-Boc-GlyGlyGly (1.359 g, 4.7 mmol) was dissolved in 350 mL of anhydrous methylene chloride at room temperature and to this solution were added DIPC (0.75 mL, 4.7 mmol), DMAP (382 mg, 3.13 mmol) and camptothecin (0.55 g, 1.57 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and left for 16 h. The solution was washed with 0.1 N HCl, dried and evaporated under reduced pressure to yield a white solid, which was recrystallized from methanol to give camptothecin-20-ester of t-Boc-GlyGlyGly: 1H NMR (DMSO-d6) δ 8.40 (s), 8.25 (d), 7.91 (d), 7.78 (m), 7.65 (t), 7.26 (s), 7.05 (br, s), 5.65 (d), 5.40 (d), 5.25 (s), 5.10 (br, s), 3.75-4.42 (m), 2.15-2.35 (m), 1.45 (s), 0.95 (t) Camptothecin-20-ester of t-Boc-GlyGlyGly (1.5 g, 1.06 mmol) was dissolved in a mixture of methylene chloride (10 mL) and TFA (10 mL) and stirred at room temperature for 1 h. Solvent was removed under vacuum and the residue was re-dissolved in methylene chloride. The solution was poured into ether to give instant precipitate (yellow). The precipitate was filtered and washed with cold ether to give 1.31 g of 12. 1H NMR (DMSO-d6) δ 8.79 (s), 7.75-8.61 (m), 7.10 (s), 5.55 (s), 3.90-4.37 (m), 3.86 (s), 3.54 (s), 2.11-2.23 (m), 0.95 (t). ESI/MS (m/z) expected 519. Found 520 (M+H).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:17]([CH3:18])[CH:16]=[CH:15][C:9]3=[N:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH2:3]1.[Cl:20][C:21]1[C:22]([NH2:29])=[N:23][C:24]([NH2:28])=[N:25][C:26]=1Cl.CCN(CC)CC>CN(C=O)C>[Cl:20][C:21]1[C:26]([NH:14][CH:12]([C:11]2[N:10]=[C:9]3[CH:15]=[CH:16][N:17]([CH3:18])[C:8]3=[CH:7][C:6]=2[N:4]2[CH2:5][C:2]([F:1])([F:19])[CH2:3]2)[CH3:13])=[N:25][C:24]([NH2:28])=[N:23][C:22]=1[NH2:29]
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Temperature: 90 °C
Reaction time: 48 h
Yield: 5.3 %

Procedure:
To a 10 mL vial were added 1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (61 mg, 0.23 mmol), 5,6-dichloropyrimidine-2,4-diamine (41.0 mg, 0.229 mmol) and Et3N (0.064 mL, 0.46 mmol) in DMF (2 mL). The resulting yellow solution was heated to 90° C. and stirred for 48 hours. The crude product was purified by preparative HPLC eluting with 30-55% ACN in water (with ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (5 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.41 (m, 3 H), 3.73-3.86 (m, 3 H), 4.17-4.35 (m, 2 H), 4.43-4.58 (m, 2 H), 5.33-5.48 (m, 1 H), 5.69-5.80 (m, 2 H), 5.89-6.01 (m, 2 H), 6.32-6.43 (m, 1 H), 6.45-6.54 (m, 1 H), 7.37-7.43 (m, 1 H), 7.45-7.51 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C17H19ClF2N8, 409; found 409.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C)C=O>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[C:12]([C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)=[O:11])=[CH:13]1
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccnc(C)c3)c(=O)c3ccccc32)c1

Procedure:
Compound 4gg was prepared following the procedure outlined in Step 3 of Example 1 using 10.4 mg (0.26 mmol) of sodium hydride (60%), 53 mg (0.20 mmol) of 3-(2-methyl-pyridine-4-carbonyl)-1H-quinolin-4-one 3h, 3 mL of anhydrous dimethylformamide, and 48 mg (0.26 mmol) of 3-methylbenzylbromide. The crude product was purified by preparative HPLC to yield 27 mg of a colorless solid 4gg: LC-MSD, m/z for C24H20N2O2, [M+H]+=369.5, [M+2H]+=370.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.605 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.35 (s, 3H), 2.61 (s, 3H), 5.40 (s, 2H), 7.00 (d, 2H), 7.15 (d, 1H), 7.25 (t, 1H), 7.35 (d, 1H), 7.39-7.46 (m, 3H), 7.60 (t, 1H), 8.40-8.46 (m, 2H), 8.60 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:34](=O)[CH2:35][CH3:36]>>[CH2:1]([O:8][C:9]1[C:10]([N:22]([CH2:34][CH2:35][CH3:36])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Reactant: CCC=O
Product: CCCCCCCOc1cc2c(cc1N(CCC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 100 %

Procedure:
Following General Procedure P, ethyl 4-(3-n-heptyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 113, 0.024 g, 0.05 mmol) was reacted with propionaldehyde to afford 0.026 g (100%) of the title compound as a yellow oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35](Cl)[CH:34]=1)[OH:32]>>[OH:32][C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][NH:29][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccccc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Example 1) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (m, 2H), 2.06 (s, 3H), 2.00-2.15 (m, 2H), 2.50-3.20 (m, 5H), 3.55-3.70 (m, 2H), 4.90-5.00 (m, 1H), 6.00-6.20 (brs, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 7.25-7.52 (m, 5H), 7.59 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 10.41 (s, 1H); MS (ES) m/z: 509.2 (MH+); HRMS Calcd. for C27H33N4O4S(MH+): 509.2223. Found: 509.2194.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.CCOCC>O1CCOCC1>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([C:4]([CH2:3][O:2][CH3:1])=[O:5])=[C:15]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: COCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Solvent: CCOCC
Product: COCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Yield: 82.8 %

Procedure:
3-methoxyacetyl-4-chloro-8-methoxyquinoline (19.0 g, 0.07 mol) and o-toluidine (9.0 ml, 0.08 mol) were heated under reflux in 1,4-dioxan (250 ml) for 1 hour. The solvent was removed and the residue taken up in dichloromethane, washed with dilute hydrochloric acid, sodium hydrogen carbonate solution, and brine. Evaporation of the solvent gave an oil, which afforded 8-methoxy-3-methoxymethylcarbonyl-4-(2-methylphenylamino)quinoline (19.5 g, 81%) as yellow crystals from ether, m.p. 122°-3°.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:31])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>C(O)C.C1COCC1>[C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Cl:31])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[C:14]=2[CH3:15])=[CH:21][CH:20]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)c3ccccc3)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(NC(=O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of [4-(4-benzoylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (130 mg, 0.29 mmol) in ethanol (3 mL) and THF (3 mL) was added a solution of sodium hydroxide (879 uL, 1.0 N) at room temperature. The resulting clear solution was stirred overnight. The solvents were removed under vacuum and the residue was diluted with water (10 mL), acidified with 1.0 N hydrochloric acid, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum afforded (115 mg, 91.3%) [4-(4-benzoylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H), 10.46 (s, 1 H), 7.91-8.04 (m, 5 H), 7.86 (s, 1 H), 7.51-7.68 (m, 3 H), 7.47 (dd, J=8.8, 1.8 Hz, 1 H), 7.23 (d, J=8.5 Hz, 2 H), 7.18 (d, J=1.8 Hz, 1 H), 3.85 (s, 2 H), 2.12 (s, 3 H). HRMS calcd. for C26H21ClNO3 [(M+H)+] 430.1205, obsd. 430.1205.
Reaction SMILES: [Cl:1][C:2]1[C:10](F)=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>Cl>[Cl:1][C:2]1[C:10]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([CH3:16])[CH2:18]2)=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC1CCCNC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1F
Agent: Cl
Product: CC1CCCN(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)C1
Reaction time: 144 h

Procedure:
A solution of 3.0 g (12 mmol) of 2-chloro-3-fluoro-4-methylsulfonylbenzoic acid in 15 mL of 3-methylpiperidine was heated at 70° C. with stirring for 6 days. The reaction mixture was diluted with aqueous hydrochloric acid and extracted with dichloromethane. The organic extract was dried over magnesium sulfate and the solvent was removed by concentration under reduced pressure. The residue obtained was crystallized from acetonitrile to obtain 2.4 g (60 percent of theory) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](O)[CH2:14][OH:15].B(F)(F)F.CCOCC>C(O)(=O)C>[CH2:14]1[O:15][CH:4]([C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[F:1])[O:5][CH2:13]1
Reactant: OCCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)c(C2OCCO2)c1
Temperature: 45 °C

Procedure:
A solution of 2-fluoro-5-nitro-benzaldehyde (25.0 g, 148 mmol), ethylene glycol (160 mL, 2.87 mol) in acetic acid (625 mL) was heated to 55° C. for 15 min. The temperature was then adjusted to 45° C., at which time BF3 -Et2O (20 mL, 20 mmol) was added dropwise (30 min). After an additional 60 min at 45° C. the solution was cooled to room temperature, and poured onto ice (1 L). The resulting solid was filtered, pressed dry, and dried in vacuo to afford the title compound as white flakes (18.81 g, 60%). MS(ES) m/e 213 [M+H]+.
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]([CH2:40][CH3:41])[C@@H:27]([C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=1)[OH:28]>>[N:1]1([C:7](=[O:24])[CH2:8][C@@H:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([NH:25][C@H:26]([C:27]([C:29]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:30]=2)=[O:28])[CH2:40][CH3:41])=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nc(-c2ccccc2)no1

Procedure:
It is similarly prepared according to general procedure given for Example 2 above but using 4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric acid and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2].[C:13](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:13])[C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c(=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)c1cnn(C)c(=O)c1
Temperature: 0 °C
Yield: 66.2 %

Procedure:
To a stirred solution of 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid ethyl ester (1.0 g, 5.9 mmol) in anhydrous DMF (15 mL) was added potassium carbonate (3.29 g, 23.8 mmol). The reaction mixture was cooled to 0° C. and methyl iodide (1.0 mL, 16 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature and was then heated at 60° C. for 15 minutes. The reaction was cooled to below 0° C. and ethyl acetate and water were added. The organic layer was separated, washed with cold water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by RP-HPLC using a linear gradient of acetonitrile in 0.1 M ammonium acetate buffer to afford the title compound (712 mg, 66%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C[O:5][C:6]([C:8]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13](=O)[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>COC(C)(C)C.O>[CH3:19][C:18]([O:17][C:15]([N:10]1[CH2:11][CH2:12][C:13]2=[N:3][N:2]([CH3:1])[C:6](=[O:5])[C:8]2([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)=[O:16])([CH3:21])[CH3:20]
Reactant: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CNN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CN1N=C2CCN(C(=O)OC(C)(C)C)CC2(Cc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Methylhydrazine is highly toxic, is a cancer suspect agent, is flammable and is potentially explosive. It should be handled with extreme care. Have spill kits, drying agents, liqua paks and fire extinguishers on hand during handling. Ensure air hoses are long enough to escape any accident scene. Since methylhydrazine can react with metal oxides, the reaction vessel was inspected to ensure that no metal surfaces were exposed prior to initiating the reaction. In a clean, glass-lined, nitrogen purged vessel, 4-oxo-3-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (prepared according to Preparation Five, Step D, 50.1 kg, 1.0 eq.) was dissolved in methyl-t-butyl ether (MTBE, 208 L) at 15° C. to 20° C. to form a solution. The reaction solution was charged with methylhydrazine (7.6 kg, 1.15 eq.). After stirring for about 30 minutes, acetic acid (13.0 kg, 1.5 eq.) was added. The reaction mixture was slowly heated to reflux temperature (53° C. to 57° C.) and held at reflux for 15 to 20 hours. The reaction was cooled to between 20° C. and 25° C. The reaction mixture was cooled to between 5° C. and 10° C. and slowly charged with 10% sodium bicarbonate solution in water (175 L). The biphasic mixture was separated and the organic layer was washed sequentially with water (175 L) and saturated sodium chloride solution (175 L). The aqueous wash layers should be combined and treated with bleach solution to destroy any residual methylhydrazine prior to disposal. The organic solution was concentrated to a volume between 130 and 170 L under partial vacuum. Addition of heptanes (174 L) to the mixture precipitated the product. The slurry was stirred for 2 hours at a temperature between 5° C. and 10C. The solids were isolated by filtration, washed with cold MTBE (34 L), and dried under vacuum at a temperature between 35° C. and 45° C. for 24 hours to give 47.1 kg of 2,3,3a,4,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid 1,1-dimethylethyl ester (95.1% yield). HPLC assay showed a product peak of 99.1% at about 5 minutes. HPLC conditions: Intersil C-8 column, 4.6×150 mm; mobile phase: 50%acetonitrile/water; aqueous phase: 1 L water, 3 mL triethylamine and 1 mL H3PO4 at pH 6.5; flow rate 1.0 mL/min.; detected by UV at 205 nm.