Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:28])[N:4]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:5]([CH3:19])=[CH:6][C:7]=1[C:8]([N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[C:3](=[O:28])[N:4]([CH2:20][C:21]([OH:23])=[O:22])[C:5]([CH3:19])=[CH:6][C:7]=1[C:8]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:9]
Reactant: Cc1cc(C(=O)N(CC(C)C)CC(C)C)c(O)c(=O)n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N(CC(C)C)CC(C)C)c(O)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 32 h

Procedure:
To a solution 3-hydroxy-4-diisobutylaminocarbonyl-6-methyl-1-tert-butyloxycarbonylmethyl-2-pyridinone from step 5 above (0.61 g) in CH2Cl2 (4 mL) was added TFA (2 mL) and the solution was stirred at ambient temperature for 32 h. The solvents were removed in vacuo to give the title compound (0.6 g; HPLC RT=13.56 min, method B).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:17][C:18]([CH3:23])([CH3:22])[C:19](Br)=[O:20].C(=O)C1C=CC=CC=1>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:19](=[O:20])[C:18]([Br:17])([CH3:23])[CH3:22])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: CC(C)(Br)C(=O)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
A solution of 4-hydroxy benzaldehyde (6.1 g, 0.050 mol) and triethylamine (6.1 g, 0.060 mol) was stirred in THF (200 mL) in a round-bottom flask. Bromoisobutyryl bromide (13.6 g, 0.060 mol) was added slowly to the stirring benzaldehyde solution, and the reaction mixture was stirred at room temperature for five hours. The white precipitate that appeared was removed by filtration, and the solvent was removed by rotary evaporation. Purification by column chromatography (eluting with 12% EtOAc in hexane) provided the desired aldehyde (6.5 g) as a white solid. 1H NMR (CDCl3) δ=2.09 (s, 6H), 7.33 (d, J=7.2 Hz, 2H), 7.96 (d, J=7.99 Hz, 2H), 10.02 (s, 1H) ppm; 13C NMR (CDCl3) δ (ppm) 30.4, 55.3, 121.5, 131.3, 134.2, 155.3, 169.6, 175.7, 190.9 ppm.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17](=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:16][C:11]3=[N:10][C:9]=2[C:24]([O:26]CC)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>C(O)C>[CH:1]1([CH2:7][C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17](=[O:23])[N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:16][C:11]3=[N:10][C:9]=2[C:24]([OH:26])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1nc2cc(C(=O)N(CC)CC)ccn2c1CC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)c1ccn2c(CC3CCCCC3)c(C(=O)O)nc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Compound 1 (947 mg, 2.46 mmol) was suspended in a 50% ethanol aqueous solution (10 mL), and the suspension was stirred at 50° C. for 1 hour after adding lithium hydroxide.1 hydrate (130 mg, 3.10 mmol). Under ice-cooled condition, 3 mol/L hydrochloric acid was added to the reaction mixture. The precipitated solid was collected by filteration, and dried under reduced pressure to give 3-cyclohexylmethyl-7-(N,N-diethylcarbamoyl)imidazo[1,2-a]pyridine-2-carboxylic acid (579 mg, yield 66%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][CH3:30])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:26]([OH:28])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(OCC)C>[F:32][C:33]([F:37])([F:36])[CH2:34][NH:35][C:26]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:25])[F:23])[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:29][CH3:30])=[O:28]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2C[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2CC1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-trifluoromethoxy-indoline-2(S)-carboxylic acid (0.432 g, 1 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.271 g, 2 mmol) were dissolved in dried dichloromethane (20 ml) under nitrogen at 0° C., and triethylamine (0.7 ml, 5 mmol) was added followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.509 g, 2 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was columned on silica gel using 8:2 dichloromethane: diethyl ether as eluent to provide an off-white solid as the desired product.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([O:16][C:17](=[O:25])[C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[CH2:9]2.[Cl-].[NH4+]>CCOCC.C1COCC1>[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([O:16][C:17](=[O:25])[C:18]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[OH:19])[CH2:9]2
Reactant: Cl[Mg]C1CCCC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccco1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclopentylmagnesium chloride, 0.0472 mol (23.6 ml of a solution 2M in ether) was added to a solution of 9.4 g (0.0377 mol) of 2-fur-2-yl-2-oxoacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester dissolved in 125 ml of THF, at −70° C. under a N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 16 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained (7.5 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia 95:5:0.5. Appropriate fractions were combined and evaporated to obtain the two diastereomers: I-14a, I-14b
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].I[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CN(C)C=O.O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:13]#[N:14])([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Reactant: IC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC2CC(C#N)(C3CCCC3)CC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a was dissolved in 30 mL of N,N-dimethylformamide followed by addition of iodo-cyclopentane (5.4 g, 27.5 mmol) and lithium hexamethyldisilazide (27.5 mL, 27.5 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 10 mL of water and concentrated to remove N,N-dimethylformamide and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyano-5-cyclopentyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 16a (2.6 g, yield 42%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([NH2:24])([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)[CH:5]=1.[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C@@H:44]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:45]Br)=[C:37]2[C:42]=1[NH:41][C:40](=[O:43])[CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[Na+].C(=O)([O-])O.[Na+]>CN1CCCC1=O.O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:44]([O:47][Si:48]([C:51]([CH3:52])([CH3:54])[CH3:53])([CH3:50])[CH3:49])[CH2:45][NH:24][C:2]([CH3:1])([CH3:23])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]34[CH2:22][CH:17]5[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]5)[CH2:20]3)[CH2:14]4)[CH:5]=2)=[C:37]2[C:42]=1[NH:41][C:40](=[O:43])[CH:39]=[CH:38]2)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: CC(C)(N)Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 120 °C
Yield: 34 %

Procedure:
To a solution of Intermediate 87 (0.981 g, 3.0 mmol) and (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (1.463 g, 2.99 mmol) in N-methylpyrrolidinone (5 mL) was added sodium iodide (0.471 g, 3.14 mmol) and sodium hydrogencarbonate (0.352 g, 4.19 mmol). The reaction mixture was heated at 120° C. for 4 hours and poured into excess water. The organic layer was extracted with diethyl ether and washed with water. The solvent was removed under reduced pressure and the crude was purified by column chromatography with silica gel, eluting with dichloromethane/methanol (from 90:1 to 90:2) to give 0.748 g (34% yield) of the title compound.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.Cl[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1>[Cu]I>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: NC(=O)c1ccccc1
Reactant: Cc1ccc(Cl)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Product: Cc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 46 h
Yield: 94.9 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (20 mg, 0.105 mmol, 5.1 mol %), benzamide (250 mg, 2.06 mmol), K2CO3 (600 mg, 4.34 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (26 μL, 0.217 mmol, 10.5 mol %) and 4-chlorotoluene (1.0 mL, 8.44 mmol) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 140° C. for 46 h. The resulting black suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 2:1; 15 mL fractions). Fractions 5-15 were concentrated, the solid residue was suspended in 10 mL of hexane and filtered to provide 413 mg (95% yield) of the product as white crystals. The 1H NMR spectrum was in accord with that reported by Erdik et al. Erdik, E.; Daskapan, T. J. Chem. Soc., Perkin Trans. 1 1999, 3139.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[C:19](#[N:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:21]1[CH2:4][CH2:3][C:2](=[CH2:7])[CH2:20][CH2:19]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC#N
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C=C1CCN([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Temperature: 100 °C

Procedure:
21.26 g (119.4 mmol) of the 4-methylenepiperidine hydrobromide (4-MP.HBr) obtained in Production 1 and 2.859 g (119.4 mmol) of lithium hydroxide were added to 80 mL of acetonitrile and stirred for a while. Thereafter, 20 g (79.6 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane was added and the mixture was heated under reflux in an oil bath (external temperature: 100° C.) for 14 hours. After the reaction completed, ethanol and distilled water were added to the reaction mixture, whereupon a crystal was precipitated. Thereafter, the crystal was filtered off, washed with 40 mL of an ethanol/water mixture, dried with air at room temperature and further dried under reduced pressure at 40° C. for 12 hours to give a pale yellow crystal of KP-103 in an amount of 24.2 g (yield, 87.3%; purity on HPLC, 95.3%).
Reaction SMILES: [CH3:1][C:2]1[C:13](C(O)=O)=[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1>ClCCl.CO.O>[CH3:1][C:2]1[CH:13]=[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nn2ccc(C(=O)O)cc2c1C(=O)O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cc2cc(C(=O)O)ccn2n1
Temperature: 150 °C
Yield: 54.8 %

Procedure:
A mixture of 2-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylic acid (1.39 g) and polyphosphoric acid (13.9 g) was stirred at 150° C. with heating for 2 hr, and ice (14 g) was added under ice-cooling, which was followed by shaking to give a homogeneous solution. The reaction mixture was adjusted to pH 4 at the same temperature and diluted with dichloromethane/methanol (4:1) and water. The precipitate was collected by filtration to give the objective compound (610 mg) as a pale-brown powder. The organic layer of the mother liquor was taken, and the aqueous layer was extracted with dichloromethane/methanol (4:1). Both organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was washed with ether to give second crystals (200 mg) as a pale-brown powder.
Reaction SMILES: C(NC/C=C\C1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)(=O)=O)C.COC([N:37]([C:52]1[C:61]([C:62]([O:64][CH3:65])=[O:63])=[C:60]2[C:55]([CH:56]3[CH2:66][CH:57]3[CH2:58][O:59]2)=[CH:54][CH:53]=1)[S:38]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1/[CH:48]=[CH:49]\[CH2:50]O)(=[O:40])=[O:39])=O.[OH:67][CH:68]1[CH2:71][NH:70][CH2:69]1>>[OH:67][CH:68]1[CH2:71][N:70]([CH2:50]/[CH:49]=[CH:48]\[C:42]2[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:41]=2[S:38]([NH:37][C:52]2[C:61]([C:62]([O:64][CH3:65])=[O:63])=[C:60]3[C:55]([CH:56]4[CH2:66][CH:57]4[CH2:58][O:59]3)=[CH:54][CH:53]=2)(=[O:39])=[O:40])[CH2:69]1
Reactant: OC1CNC1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Agent: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC(O)C2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and 3-hydroxyazetidine as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[S:24]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])(=[O:25])=[O:26]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: OCC1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
Piperidin-2-yl-methanol (17.39 mmol, 1 eq) was dissolved in methylene chloride (20 ml) and triethylamine (43.47 mmol, 2.5 eq) at 0° C. and a solution of 2-chloro-6-methyl-benzenesulfonyl chloride (17.39 mmol, 1 eq) in methylene chloride (65 ml) was added dropwise. The reaction solution was stirred at room temperature for 90 min. 0.5 M HCl (75 ml) was then added and the mixture was stirred for a further 15 min. The organic phase was washed with water (10 ml), dried over sodium sulfate and concentrated to dryness under reduced pressure. Yield: 90%
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1>C1(C)C=CC=CC=1>[C:2]1([CH:1]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCNC1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NC1CCCNC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Benzaldehyde (21.2 g; 0.2 mol) was added, dropwise, to a solution of 3-aminopiperidine (20 g; 0.2 mol) in toluene (80 ml). The solution thus obtained was stirred at room temperature, After 3 h the solvent was removed by evaporation at reduced pressure and the residue was taken up twice with toluene. 29 g N-(phenylmethylene)piperidine-3-amine was thus obtained, and was used in the subsequent reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:5][CH:4]=1.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:28][C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: COc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(4-Methoxyphenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].O=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH:18]=2)[CH2:13][CH2:12]1.[ClH:34]>CO>[ClH:34].[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[S:21]([NH:20][C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][C:11]2=[N:5][NH:6][C:7](=[NH:9])[NH2:8])=[CH:15][CH:16]=1)(=[O:23])=[O:22]
Reactant: O=C1CCc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc21
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CO
Product: N=C(N)NN=C1CCc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc21
Yield: 36 %

Procedure:
Aminoguanidine hydrogencarbonate (45 mg, 0.33 mmol) was dissolved in 2 ml of 1 N HCl. A solution of N-(3-oxo-2,3-dihydro-1H-inden-5-yl)naphthalene-2-sulfonamide (100 mg, 0.30 mmol) in methanol (2 ml) was added and the mixture was heated to reflux for 1 hour. Then the mixture was concentrated in vacuo and the precipitated salt was crystallized from acetonitrile to give 48 mg (36%) of 2-{6-[(2-naphthylsulfonyl)amino]-2,3-dihydro-1H-inden-1-ylidene}hydrazinecarboximidamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: Cc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)c1
Temperature: 150 °C
Yield: 83.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3-methylphenyl)-3-piperidinecarboxamide (90 mg, 0.209 mmol), 3 mL of EtOH, Hunig's base (0.11 ml, 0.627 mmol), and hydrazine anhydrous (0.026 ml, 0.836 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes in microwave. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (77 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 1H), 1.84 (m, 2H), 2.07 (m, 1H), 2.27 (s, 3H), 3.50 (m, 1H), 4.48 (m, 2H), 4.75 (m, 1H), 4.90-5.13 (m, 1H), 6.87 (s, 1H), 6.94-7.08 (m, 1H), 7.13-7.26 (m, 1H), 7.41 (m, 6H), 7.75 (s, 1H), 7.83-8.00 (m, 1H), 10.00 (s, 1H), 12.07 (s, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]([NH2:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH3:5][CH:6]([NH:13][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC(C)N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCC(C)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of acetyl chloride (7.11 mL, 100 mmol) was added dropwise to an ice water-cooled solution of 1-methylheptyl amine (8.30 g, 64 mmol) and triethylamine (20.91 mL, 150 mmol) in THF (100 mL). The resulting mixture was stirred at RT for 1 h, then was diluted with ethyl acetate and washed twice with 10% HCl, twice with sat aq NaHCO3, and then twice with brine. The organic solution was dried (MgSO4), and concentrated to afford 8.13 g N-(1-methylhept-1-yl)acetamide, a 73% yield.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[C:24]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1)(=[O:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCC(O)c1ccc(C=O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCCCCCCC(=O)c1ccc(C=O)cc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Dess-Martin periodinane (0.268 g, 0.632 mmol) was added to a solution of 4-(1-hydroxynon-1-yl)benzaldehyde (0.125 g, 0.505 mmol) from Step A in CH2Cl2 (3.0 ml). After 1 h, the reaction was filtered and concentrated. Silica gel chromatography eluting with 19:1 v/v hexane/EtOAc gave 0.107 g (0.446 mmol, 88%) of the title compound: 1H NMR (500 MHz) δ 10.1 (s, 1H), 8.10 (d, J=8.2, 2H), 7.97 (d, J=8.2, 2H), 3.00 (t, J=7.3, 2H), 1.70-1.8 (m, 2H), 1.22-1.42 (m, 10H), 0.88 (t, J=7.0, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18](=[O:28])[NH:17][CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)(=O)C.[H-].[Na+].Br[CH2:32][CH2:33][OH:34]>CN(C=O)C.C(OCC)(=O)C.O>[OH:34][CH2:33][CH2:32][N:17]1[CH:16]=[CH:15][C:14]2[N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=3)[C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][C:19]=2[C:18]1=[O:28]
Reactant: OCCBr
Reactant: CC(=O)OCc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1c2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2ccn1CCO
Reaction time: 24 h

Procedure:
To a solution of 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl acetate (see preparation of 3-4 for this intermediate) (74 mg, 0.20 mmol) in dry DMF (1 mL) was added 60% sodium hydride in mineral oil (57 mg, 1.4 mmol). After 10 minutes 2-bromoethanol (50 μL, 0.71 mmol) was added to the reaction which was monitored over 24 hours by LC/MS. Two more portions of 2-bromoethanol were added during this period. The reaction was diluted with ethyl acetate and water. After stirring for 0.5 hour, the organic layer was isolated and washed with aqueous NaHCO3, dried (anhydrous Na2SO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with 30-100% ethyl acetate and then 0.25-1.5% methanol/ethyl acetate (sat'd with NH3) to give the title compound. 1H-NMR (500 MHz, CDCl3): δ 8.68 (1H, s), 7.47 (1H, d, J=7.8 Hz), 7.39 (2H, d, J=8 Hz), 7.27-7.31 (5H, m), 7.20-7.22 (2H, m), 6.89 (1H, d, J=7.5 Hz), 4.65 (2H, s) 4.19 (2H, t, J=5.3 Hz), 3.94 (2H, t, J=5.3 Hz) m/e (m+1): 373.2.