Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:11].NC1C=CC(C#N)=CC=1OC1C=CC=CC=1Br.[CH2:30]([N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:40]2[CH2:39][CH2:38][N:37]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:42][CH2:41]2)[C:5]=1[OH:11]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[N+](C)(C)C
Product: COC(=O)c1cccc(NC2CCN(Cc3ccccc3)CC2)c1O

Procedure:
Using an adaptation of the method described in Procedure 3, substituting 3-amino-2-hydroxybenzoic acid methyl ester, 1l for 4-amino-3-(2-bromophenoxy)-benzonitrile, 2a, 1-benzylpiperidin-4-one for 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, and tetramethylammonium triacetoxyborohydride for sodium triacetoxyborohydride, the title compound 3-(1-benzylpiperidin-4-ylamino)-2-hydroxybenzoic acid methyl ester, 2l was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+]>CO>[CH3:12][NH:13][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CN
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-3-carboxaldehyde (5.4 g, 34.1 mmole) in MeOH (30 mL) was added a solution of 2.0 M CH3NH2 m MeOH (51.3 mL, 102.6 mmole). The reaction was stirred at RT overnight, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (40 mL), and NaBH4 (1.3 g, 34.1 mmole) was added. After 16 hrs the reaction was concentrated to a slurry and dissolved in 10% Na2CO3 (100 mL). The aqueous solution was extracted with EtOAc (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Drying in high vacuum left the title compound (5.2 g, 94%) as a faintly yellow oil: MS (ES) m/e 161 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(F)ccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2cc(F)ccc21
Yield: 41.6 %

Procedure:
5-Fluoro-2,3-dihydro-1H-inden-1-one (I-78c: 1.2 g, 8.0 mmol) in TFA (20 mL) was reacted with sodium azide (1.7 g, 26.4 mmol) to afforded 550 mg of the product (46.2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:49]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:48][NH:47][N:46]=2)=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:49]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:48][N:47]([C:13](=[O:15])[CH2:12][CH:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH3:16])[N:46]=2)=[CH:43][CH:44]=1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: CC(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CC(=O)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.1 %

Procedure:
To a stirred mixture of 3-((4-chlorophenyl)sulfonyl)butyric acid (1.85 gram, 7.00 mmol), diisopropylethylamine (3 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.50 gram, 15.7 mmol) was added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3.00 gram, 11.7 mmol) and the resulting mixture was stirred for 16 hours at room temperature. After concentration in vacuo the resulting residue was purified by flash chromatography (petroleum ether/diethyl ether=1/2 (v/v), followed by diethyl ether) to give 3-(4-chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)butanoyl]-4,5-dihydro-4-phenyl-1H-pyrazole (3.69 gram, 63% yield) as a diastereomeric mixture. Melting point: amorphous.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>C(#N)CC>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:44][CH2:43]2)=[CH:40][CH:41]=1
Reactant: CC(C)N1CC(=O)Nc2cc(CO)cnc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)N1CC(=O)Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
The 7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.452 mmol) was weighed into a vial and taken up as a suspension in propiononitrile (1 mL). Next was added (cyanomethyl)trimethylphosphonium iodide (132 mg, 0.542 mmol) followed by DIEA (0.237 mL, 1.356 mmol). To the stirred white suspension was then added the 1-(4-chlorophenyl)piperazine hydrochloride (116 mg, 0.50 mmol). The reaction was stirred overnight at 90° C. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in DMSO (3 mL) and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (46.6 mg, 26%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.74-4.87 (m, 1H), 3.81 (s, 2H), 3.33 (d, J=2.0 Hz, 2H), 3.01-3.15 (m, 4H), 2.41-2.48 (m, 4H), 1.12 (d, J=6.8 Hz, 6H). [M+H] calc'd for C21H26ClN5O, 400; found, 400.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:23])[CH2:16][CH2:17][C:18]([O:20]CC)=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[O:23][C:18](=[O:20])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(O)CCC(=O)OCC)cc1
Solvent: CCOCC
Product: CCCCCCCOc1ccc([C@@H]2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.5 %

Procedure:
Ethyl 4-(4-heptyloxyphenyl)-4-hydroxybutanoate (17 g), porcine pancreatic lipase (hereinafter abbreviated to PPL) (34.4 g) and anhydrous diethyl ether (500 ml) were placed in a 1 l three-necked flask(followed by agitating the mixture at room temperature for 4 days, filtering off PPL, concentrating the filtrate under reduced pressure, and purifying the concentrate according to chromatography, to obtain rel-(S)-γ-(4-heptyloxyphenyl)-γ-butyrolactone (4 g) (69% e.e., optical purity (%) was measured by Chiral Cell OB made by Daisel Co., Ltd., e.e.: abbreviation of enantiomer excess, hereinunder this applies to) and ethyl rel-(R)-γ-(4-heptyloxyphenyl)hydroxybutanoate (5.2 g) ([α]D26.0 -13.69 (c 10.24, chloroform)). The former was recrystallized from ethanol, followed by removing the resulting crystals, concentrating the mother liquor under reduced pressure and recrystallizing the concentrate from ethanol to obtain rel-(S)-γ-(4-heptyloxyphenyl)-γ-butyrolactone (3.8 g) (95% e.e.). m.p.: 44.0° C., [α]D31.6 +6.62 (c 11.89, chloroform).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CCCOCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COCCC[C@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl 3(S)-[3-(benzyloxy)propyl]pyrrolidine-1-carboxylate (495 mg, 1.55 mmol) in 6 mL of CH2Cl2 was added CF3COOH (1.5 mL) at room temperature under N2. The resulting solution was stirred for 3 h at room temperature and then concentrated under vacuum. To the residue was added 20 mL of water, and the solution was washed with 30 mL of petroleum ether. The water layer was adjusted to pH 8.0 with 2 M aqueous NaHCO3 solution and extracted with CH2Cl2 (3×40 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to give 3(S)-[3-(benzyloxy)propyl]pyrrolidine (330 mg, 97%) as a yellowish oil. LC-MS (ESI) m/z 220 (M+H+).
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].[OH-].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[CH2:19]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCOCCOCCOCCOCCO
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
To Compound 1 (5.2 g, 21.8 mmol), potassium hydroxide (1.2 g, 21.4 mmol) was added; this was followed by stirring on an oil bath at 130° C. for 15 minutes, after which the oil bath was removed and benzyl chloride (2.7 g, 21.3 mmol) was gradually added. This was again heated to 130° C. and stirred for 2 hours. After the solution was allowed to cool to room temperature, water was poured to stop the reaction, and extraction from methylene chloride was conducted. The combined organic phases were dried with sodium sulfate, filtered, and concentrated under reduced pressure, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate—5% methanol-ethyl acetate solution) to yield Compound 19 (light-yellow oil 2.3 g, 32%).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][C:41]([S:45][CH3:46])=[CH:40][C:39]=4[F:47])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO.C1COCC1.C(Cl)Cl>[NH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:13]2[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:39]([F:47])=[CH:40][C:41]([S:45][CH3:46])=[CH:42][C:43]=4[F:44])[N:32]=3)=[O:30])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CSc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.3 mg, 0.009 mmol) was dissolved in MeOH (0.1 mL) and THF (0.06 mL), then 1.0 M aq. NaOH (0.038 mL, 0.038 mmol) was added. The reaction mixture was stirred at room temperature for 20 min. The organic solvents and trace of water were removed under reduced pressure to give a crude intermediate. The residue was dissolved in DCM (0.1 mL) and then TFA (0.095 mL, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 20 min., then the solution was evaporated under reduced pressure. The residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)), the diastereoisomers of the product had the following properties:
Reaction SMILES: [Li]CCCC.CCCCCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[O:20][CH3:21].Br/[CH:23]=[CH:24]\[C:25](OCC)=[O:26].CC(C[AlH]CC(C)C)C>C1COCC1.[Cl-].[Zn+2].[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:12][C:13]1[C:14]([O:20][CH3:21])=[C:15](/[CH:23]=[CH:24]\[CH2:25][OH:26])[C:16]([F:19])=[CH:17][CH:18]=1
Reactant: CCOC(=O)/C=C\Br
Reactant: COc1cc(F)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(F)ccc(F)c1/C=C\CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Solution of BuLi (2.5M) in hexane (9.6 ml; 0.024 mol) was added to a stirred solution of 2,5-difluoroanisol (2.88 g, 0.02 mol) in dry THF (30 ml) at −70 C, followed after 2 h by solution of zinc chloride (3.6 g; 0.026 mol) in dry THF (50 ml). The reaction temperature was allowed to raise to room temperature and then stirring was maintained at room temperature for 30 min. Pd(OAc)2 (8 mg; 0.2 mol %) was added, followed by ethyl cis-3-bromoacrylate (3.58 g; 0.02 mol). The reaction mixture was placed in preheated oil bath and heated under reflux for 1 h. The resulting reaction mixture was chilled to −78 C and 60 ml (0.06 mol) of DIBAL (1M solution in hexanes) was added dropwise. The stirring was continued at −78 C for 2 h and 1 h at room temperature. The reaction was quenched with water and all solids were dissolved by addition of HCl. The organic phase was diluted with ether, separated, washed with 5N HCl, brine and evaporated in vacuo. The residue was Kugelrohr distilled (1.5×10−2 mbar, 150 C) to give 3.7 g (92%) of crude (2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol, which contains ˜6% of other regioisomers. The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CC1Cc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1Cc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-3,6-dihydropyridine-1(2H)-carboxylate (0.26 g, 0.50 mmol) in methanol (5 mL) was added palladium on carbon 10% wt. (52 mg) under an atmosphere of nitrogen. The mixture was vacuumed and re-charged with hydrogen three times, and stirred at r.t. for 48 h. The mixture was filtered. The filtrate was concentrated to afford the desired product which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=522.4.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[BH4-].[Na+]>CO>[C:4]1([CH2:5][NH:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:7]=[CH:8][CH:9]=[C:2]([CH2:1][NH:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCNCCCN
Reactant: O=Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCNCCCNCc1cccc(CNCCCNCCCNC(=O)OC(C)(C)C)c1
Reaction time: 24 h

Procedure:
Isophthalaldehyde (1.07 g, 7.99 mmol) and MeOH (50 mL) were added to a round-bottom flask. To the solution was added tert-butyl (3-((3-aminopropyl)amino)propyl)carbamate (3.69 g, 16.0 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (1.21 g, 32.0 mmol) was added portionwise and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and aq. NaOH (10%, 150 mL) and EtOAc (150 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (150 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as a clear oil. The intermediate was carried forward without further purification.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:20]1([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl.C(Cl)(Cl)[Cl:31].CO>O1CCOCC1.C(O)(=O)C>[NH:1]([Cl:31])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:20]1([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)[C@H](Cc1ccccc1)NCl
Yield: 100 %

Procedure:
Boc-Phe-morpholinamide (12.8 g, 38 mmol) was placed in a 250 ml flask, then 4N HCl in dioxane (30 ml) was added. The mixture was stirred for six hours at which time TLC (silica gel; CHCl3 :MeOH:acetic acid, 90:8:2) indicated that the reaction was completed. Dioxane and excess HCl were removed. A white solid, identified by 1HNMR as HCl-Phe-morpholinamide, was obtained in 100 percent yield (10.3g, 38 mmol).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[CH3:2].C(N(CC)CC)C.C(Cl)Cl.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O>[CH2:20]([O:19][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)(=[O:40])=[O:39])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
2.18 g (10 mmol) of 2-methoxy-3,4-methylenedioxybenzylamine hydrochloride (1) and 3.06 ml (22 mmol) of triethylamine were added to 30 ml of methylene chloride. Then, 1.91 g (10 mmol) of p-toluene sulfonyl chloride was added portionwise under water-cooling. The resulting mixture was stirred at room temperature for one hour. 20 ml of water was added for liquid separation. The methylene chloride layer was washed with 15 ml of water and dried over anhydrous magnesium sulfate followed by filtration thereof. The solvent was distilled off under vacuum. 30 ml of n-hexane was added to the residue and stirred for 30 minutes. The resulting crystals were collected by filtration, washed with n-hexane and dried to obtain 3.25 g of N-(2-methoxy-3,4-methylenedioxybenzyl)-p-toluenesulfonic amide (2) (yield 97%). It was recrystallized from ethyl acetate, m.p. 150°-151° C. IR and NMR spectra of the resultant product are listed below. ##STR31##
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:32]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Product: Cc1ccc(C(OC2CN(C(=O)NC3CCCCC3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]azetidine hydrochloride (151) (0.56 mmol) and cyclohexyl isocyanate (0.56 mmol) using the procedure described for compound (10). The desired product was obtained as a white foam (230 mg, 91%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[N:6][N:5]2[C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([N:10]4[CH2:15][CH2:14][CH:13]([N:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[CH2:12][CH2:11]4)=[N:6][N:5]3[C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[N:24][CH:23]=2)[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Brc1nc2ccc(N3CCC(N4CCCC4)CC3)nn2c1-c1ccnnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1cc(F)cc(-c2nc3ccc(N4CCC(N5CCCC5)CC4)nn3c2-c2ccnnc2)c1
Yield: 38.2 %

Procedure:
A mixture of 0.090 g (0.21 mmol) of 2-bromo-3-pyridazin-4-yl-6-(4-pyrrolidin-1-ylpiperidin-1-yl)imidazo[1,2-b]pyridazine, 0.014 g (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium and 0.043 g (0.27 mmol) of 3,5-difluorophenylboronic acid and of a 2M aqueous solution of cesium carbonate in 2 ml of dioxane is heated at 120° C. for 20 minutes in a microwave oven. 1 ml of a saturated aqueous solution of sodium chloride and 4 ml of ethyl acetate are then injected into the tube. After stirring, the organic phase is removed with a syringe and passed over a sodium sulfate cartridge. The solution is directly injected onto a silica gel column and chromatographed, elution being carried out with a mixture of 0 to 10% of methanol in dichloromethane. 0.037 g of product is thus isolated.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])[S:5][C:6]=1[CH3:7].CC(C)([O-])C.[K+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:4](=[N:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])[S:5][C:6]=1[CH3:7]
Reactant: ClCc1ccncc1
Reactant: Cc1nc(NC(=O)C23CC4CC(CC(C4)C2)C3)sc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(Cc2ccncc2)c1C
Temperature: 250 °C
Yield: 36.7 %

Procedure:
To a solution of Example 97A (145 mg, 0.50 mmol) in DMF (5 mL) was added potassium tert-butoxide (120 mg, 1.10 mmol) and the hydrochloride salt of 4-chloromethyl-pyridine (82 mg, 0.5 mmol). The mixture was heated in a SmithSynthesizer™ microwave at 250° C. for 15 minutes. The mixture was diluted with ethyl acetate, washed with 1M NaHCO3, and layers were separated. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was recrystallized from ethyl acetate to afford the title compound (70 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.72 (m, 6 H), 1.75 (d, J=2.4 Hz, 6 H), 1.91 (s, 3 H), 2.09 (d, J=0.7 Hz, 3 H), 2.17 (d, J=0.7 Hz, 3 H), 5.44 (s, 2 H), 7.06-7.20 (m, 2 H), 8.50-8.56 (m, J=6.1 Hz, 2 H); MS (ESI+) m/z 382 (M+H)+; Anal. Calculated for C22H27N3OS.0.2H2O: C, 68.61; H, 7.17; N, 10.91. Found: C, 68.56; H, 7.12; N, 10.76.