Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[C:15]1([CH:21]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:22][NH:23][C:24]2[N:32]=[C:31](SC)[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:47](=O)([O-])O.[Na+]>O.CC(C)=O>[C:41]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][NH:23][C:24]2[N:32]=[C:31]([S:3]([CH3:47])(=[O:5])=[O:2])[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C([O-])O
Reactant: CSc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1

Procedure:
A solution of oxone® (potassium peroxymonosulphate) (44 g, 71.7 mmol) in water (200 ml) was added drop wise over 2 hr to a stirred solution of N-(2,2-diphenylethyl)-2-(methylsulfanyl)-9-tetrahydro-2Hpyran-2-yl-9H-purin-6-amine (preparation 7) (25 g, 56.2 mmol) and sodium hydrogen carbonate (20 g, 238 mmol) in acetone (1000 ml) and water (250 ml). The resultant mixture was stirred at room temperature for 24 hr, filtered and the residue washed with acetone. The acetone was removed from the filtrate under reduced pressure and the resulting aqueous residue extracted with ethyl acetate and then dichloromethane. The combined organic extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was triturated with diethyl ether, the mixture filtered and the collected material washed with diethyl ether and pentane, then dried to afford the title compound as a white solid (20.32 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH2:24].Cl>C(#N)C.O1CCOCC1>[ClH:1].[CH:9]1([NH:8][C:6]2[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=[C:2]([NH:24][CH2:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NCc1ccccn1
Reactant: Cc1nc(Cl)nc(NC2CCCCC2)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a stirred solution of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine (0.1 g, 0.40 mmol) and (pyridin-2-ylmethyl)amine (0.04 g, 0.400 mmol) in acetonitrile (5 mL) was added a 3.5 M solution of hydrogen chloride in dioxane (0.2 mL). The resulting mixture was irradiated in CEM Focused Microwave™ Synthesis System at 160° C. for 120 minutes. The resulting mixture was cooled to ambient temperature. The formed precipitate was collected by filtration and dried to yield 0.07 g (48.2%) of the titled compound as the hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.03 (m, 2H), 1.13 (d, J=12.63 Hz, 1H), 1.20-1.26 (m, 2H), 1.51-1.59 (m, 2H), 1.60-1.63 (m, 3H), 1.89 (s, 3H), 2.24 (s, 3H), 3.70 (s, 1H), 4.62 (d, J=5.10 Hz, 2H), 7.24 (dd, J=7.25, 4.84 Hz, 1H), 7.31 (d, J=7.79 Hz, 1H), 7.58 (d, J=7.72 Hz, 1H, 7.74 (t, J=7.66 Hz, 1H), 8.1 (s, 1H), 8.50 (d, J=4.84 Hz, 1H); MS (ESI) m/z 312.3 (M+1)+.
Reaction SMILES: P(I)(I)OP(I)I.[C:8]([NH:27][C:28]1[S:29][CH:30]=[C:31]([C:33](=[N:56][O:57][CH3:58])[C:34]([NH:36][CH:37]2[C:44](=[O:45])[N:43]3[CH:38]2[CH2:39][S:40][CH:41]([CH2:54][CH3:55])[C:42]3(O)[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:35])[N:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([NH:27][C:28]1[S:29][CH:30]=[C:31]([C:33](=[N:56][O:57][CH3:58])[C:34]([NH:36][CH:37]2[C:44](=[O:45])[N:43]3[CH:38]2[CH2:39][S:40][C:41]([CH2:54][CH3:55])=[C:42]3[C:46]([O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:47])=[O:35])[N:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC1SCC2C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N2C1(O)C(=O)OC(C)(C)C
Agent: IP(I)OP(I)I
Solvent: c1ccncc1
Product: CCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2CS1
Yield: 32.5 %

Procedure:
Using the procedure of Example 1, 560 mg of diphosphorous tetraiodide, 4.5 ml of pyridine and 394 mg of the product of Step B were reacted to obtain 125 mg of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-ethyl-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate.
Reaction SMILES: [Cl-:1].[NH4+].[NH2:3][C:4]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:5]=1[O:6][CH2:7][CH:8]([OH:11])[CH2:9][NH2:10]>O.[Zn]>[ClH:1].[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:5]=1[O:6][CH2:7][CH:8]([OH:11])[CH2:9][NH2:10]
Reactant: [Cl-]
Reactant: NCC(O)COc1cc([N+](=O)[O-])ccc1N
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: Cl
Product: NCC(O)COc1cc(N)ccc1N

Procedure:
7.5 g of zinc powder and a solution of 0.3 g of ammonium chloride in 1.5 ml of water are added to 15 ml to 96° strength alcohol. The mixture is heated to the reflux temperature, with stirring, and 0.015 mol (3.4 g) of the 1-(2'-amino-5'-nitrophenoxy)-3-aminopropan-2-ol prepared according to Example 5 is then added gradually so as to maintain the reflux without external heating. When the addition has ended, the reflux is maintained for 5 minutes and the boiling reaction medium is then filtered into 4.6 ml of iced hydrochloric acid (specific gravity=1.18). The expected product crystallises in the form of the trihydrochloride. The product is filtered off, washed with alcohol and dried in vacuo. It melts with decomposition at 216°-218° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([NH:29][N:30]([C:32]1[CH:37]=[C:36]([C:38]#[N:39])[CH:35]=[CH:34][C:33]=1[F:40])C)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[F:40][C:33]1[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:32]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(NC(=O)OC(C)(C)C)c1cc(C#N)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1c2c(c(=O)n1-c1cc(C#N)ccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 9.9 %

Procedure:
Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 1.00 g, 4.7 mmol) of in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(5-cyano-2-fluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (700 mg, 2.6 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was heated in an oil bath at 50° C. for 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 6 mL, 24 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. The solvent was evaporated and the residue was purified by preparative HPLC to give a yellow foam. This was triturated with ether and then petroleum ether and the solvent was removed. The residue was co-evaporated with methanol and the petroleum ether and then further purified on an ISCO system, eluting with 50-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated successively with methanol, diethyl ether, and petroleum ether, and then dried under high vacuum at room temperature to give 4-fluoro-3-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-yl)-benzonitrile (84 mg, 10%) as a white foam. APCI(+)-MS (M+H) 326.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (570 mg) in THF (5 mL) were added triphenylphosphine (447 mg) and water (1 mL), and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/methanol) to give the title compound (477 mg).
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H:2](C(O)=O)C.[NH:17](C(OCC1C=CC=CC=1)=O)[C@H:18](C(O)=O)[CH:19]([CH3:21])[CH3:20].[NH:35]([C:44]([O:46]CC1C=CC=CC=1)=O)[C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH:38]([CH3:40])C.N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)CC1C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)CCSC.N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)CCCC>>[NH2:17][C@H:18]([C:44]([N:35]1[CH2:40][CH2:38][CH2:37][C@H:36]1[C:41]([O:43][CH3:2])=[O:42])=[O:46])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C

Procedure:
Instead of Z-Ala-OH, (a) Z-Val-OH, (b) Z-Leu-OH, (c) Z-Phe-OH, (d) Z-Met-OH and (e) Z-norLeu-OH were used as starting compounds to obtain (a') H-Val-Pro-OMe, (b') H-Leu-Pro-OH, (c') H-Phe-Pro-OH, (d') H-Met-Pro-OMe and (e') H-norLeu-Pro-OMe as oils, respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:27][C:2]1([CH3:1])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:21]([CH:26]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)CCN
Reactant: CC1(C)CC(C(Nc2cnc3ccccc3c2)c2ccc(C(=O)O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3ccccc3c2)C2CC(C)(C)C2)cc1
Reaction time: 18 h
Yield: 66.4 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoic acid (14.0 mg, 0.0390 mmol) was added 3-aminopropionic acid ethyl ester hydrochloric (6.60 mg, 0.0430 mmol), 1-Hydroxy-7-azabenzotriazole (6.40 mg, 0.0470 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (9.00 mg, 0.0470 mmol). Anhydrous methylene chloride (0.390 mL) was added followed by triethylamine (0.007 mL, 0.0510 mmol). After 18 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 26.0 mg of crude material. Purification by column chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzamido)propanoate (11.9 mg, 66% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ: 8.48 (d, J=2.7 Hz, 1H), 7.88 (dd, J=8.3, 1.3 Hz, 1H), 7.74-7.67 (m, 2H), 7.46-7.41 (m, 2H), 7.41-7.29 (m, 3H), 6.81 (t, J=6.1 Hz, 1H), 6.69 (d, J=2.7 Hz, 1H), 4.42 (br. s., 1H), 4.25 (dd, J=9.3, 4.4 Hz, 1H), 4.19-4.08 (m, 2H), 3.70 (q, J=6.0 Hz, 2H), 2.61 (t, J=5.7 Hz, 2H), 2.59-2.45 (m, 1H), 2.07-1.97 (m, 1H), 1.76-1.67 (m, 2H), 1.66-1.55 (m, 1H), 1.28-1.21 (m, 3H), 1.13 (s, 3H), 1.09 (m, 3H). MS (M+1): 460.4.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.O.[NH2:11][NH2:12].[C:13]1([N:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)SCC)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:20]2[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:2]([F:1])([F:8])[F:9])=[N:12][N:11]=2)=[CH:25][CH:26]=1
Reactant: CCSC(=Nc1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Fc1ccc(-c2nnc(C(F)(F)F)n2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 27 %

Procedure:
First, 3.0 g of ethyl trifluoroacetate and 10 mL of 1-butanol were put in a 100 mL three-neck flask and stirred with being cooled with ice for 10 minutes. After the stirring, 1.1 g of hydrazine monohydrate was added to this mixed solution, and the solution was stirred for 30 minutes while the temperature was increased to room temperature. Then, 5.1 g of ethyl N-phenyl-4-fluorobenzenecarboximidothioate was added to this reacted solution, and the reacted solution was heated and refluxed at 130° C. for 5 hours. After the reflux, 1-butanol was distilled off under a reduced pressure to give an oily substance. The given oily substance was purified by silica gel column chromatography. A mixed solvent of toluene:ethyl acetate=4:1 (v/v) was used as a developing solvent. The obtained fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of ethanol and hexane, so that 3-(4-fluorophenyl)-4-phenyl-5-trifluoromethyl-4H-1,2,4-triazole (abbreviation: HCF3Fptz) was prepared (a white solid, yield: 27%). The synthetic scheme of Step 1 is shown by (a-3).
Reaction SMILES: ClC1C=C2CN(C(OC(C)(C)C)=O)[C@@H](C(C)C)C2=NC=1.CS(O[CH:26]([C:28]1[C:29]([C@@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:36]([CH3:38])[CH3:37])=[N:30][CH:31]=[C:32]([Cl:34])[CH:33]=1)[CH3:27])(=O)=O>>[Cl:34][C:32]1[CH:33]=[C:28]2[CH:26]([CH3:27])[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:35]([CH:36]([CH3:38])[CH3:37])[C:29]2=[N:30][CH:31]=1
Reactant: CC(OS(C)(=O)=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: CC(C)[C@H]1c2ncc(Cl)cc2CN1C(=O)OC(C)(C)C
Product: CC(C)[C@H]1c2ncc(Cl)cc2C(C)N1C(=O)OC(C)(C)C
Reaction time: 0.02 h

Procedure:
Procedure same as that for tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, using 1-(2-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)ethyl methanesulfonate as a starting material. LC-MS tR=1.12 min in 1 min chromatography, MS (ESI) m/z 311.4 [M+H]+. 1H NMR (CDCl3, 400 MHz, mixture of diastereomers): δ 8.43 (d, J=1.6 Hz, 1H), 7.52 (s, 0.7H), 7.46 (s, 0.3H), 5.05-5.00 (m, 1H), 4.94 (s, 0.3H), 4.81 (s, 0.7H), 2.88-2.39 (m, 0.3H), 2.32-2.08 (m, 0.7H), 1.55 (m, 3H), 1.44 (s, 9H), 1.26 (d, J=7.2 Hz, 0.9H), 1.09 (broad s, 2.1H), 0.81 (broad s, 2.1H), 0.48 (d, J=7.2 Hz, 0.9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[NH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH:22][C:33]([C:29]2[CH:28]=[C:27]3[C:32]([C:24]([Cl:23])=[CH:25][NH:26]3)=[CH:31][CH:30]=2)=[O:34])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CCCC[C@@H](N)COCC1CCN(C(=O)OC(C)(C)C)CC1
Product: CCCC[C@H](COCC1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using coupling method A, 4-[(R)-2-amino-2-(butyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (195 mg, 0.62 mmol) and 3-chloroindole-6-carboxylic acid (133 mg, 0.68 mmol) afforded, after purification (SiO2: 40% EtOAc in hexane), 90 mg (29%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.[OH-].[NH4+].Cl>O.CO.N1C=CC=CC=1>[OH:8][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:23]([C:13]23[CH2:22][CH:17]4[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]4)[CH2:20]2)[CH2:14]3)=[O:24])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: O=C(NCCc1ccc(O)c(O)c1)C12CC3CC(CC(C3)C1)C2
Reaction time: 5 h

Procedure:
Dissolve 15.0 g. of dopamine hydrochloride in 200 ml. of pyridine. With stirring, add 47.8 g. of 1-adamantane carboxylic acid chloride portionwise over a 2-hour period at room temperature. Stir at room temperature overnight. Add methanol (200 ml.), water (75 ml.) and concentrated ammonium hydroxide solution (50 ml.) to the reaction mixture and allow the clear solution to stand for 5 hours at room temperature. Pour the solution into 2 liters of 2N hydrochloric acid and ice with vigorous agitation. Extract the oily precipitate with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate solution, dry over sodium sulfate and evaporate to a residue. Remove the last traces of ethyl acetate in vacuo and crystallize the product from acetone-ether to obtain the title product, m.p. 198°-200°C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(NC(C)C)(C)C.C([Li])CCC.[C:25](O)(=O)[C:26](O)=[O:27]>CCCCCC.C(N=CC)(C)(C)C.ClP(=O)(OCC)OCC.O1CCCC1>[CH2:5]([C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:25][CH:26]=[O:27])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: O=C(O)C(=O)O
Reactant: CCCCCC(=O)CCCCC
Agent: CC=NC(C)(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCCCCC(=CC=O)CCCCC
Reaction time: 72 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction was worked up after 3 days. The following reagents were used: 6-undecanone (17 g), diisopropylamine (32.2 mL), 1.6M n-butyl lithium in hexane (143 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofuran (200 mL). The work up, varied only in that the oxalic acid catalyzed hydrolysis was run overnight at room temperature, gave the crude aldehyde which was purified by HPLC (ether-hexane; 1:16.6) to yield 15.5 g of 3-pentyl-2-octenal as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>[Pd].C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2Cc2ccccn2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2CC2CCCCN2)cc1

Procedure:
Reduction of 2'-(2-pyridylmethyl)-p-anisanilide (4.65 g., 0.0146 mole) according to the procedure of Walker, J. Org. Chem., 27, 2966 (1962), in 150 ml. of acetic acid with 2.35 g. of 10% palladium on carbon catalyst affords 2'-(2-piperidylmethyl)-p-anisanilide, m.p. 108°-109° C. (corr.), from benzene-hexane.
Reaction SMILES: [F:1][C:2]1([F:16])[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:28]1[N:29]=[C:30]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[C:40](F)[CH:41]=[C:42]([F:47])[CH:43]=3)[N:38]=2)[N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12>CN(C=O)C>[N:28]1[N:29]=[C:30]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[C:40]([O:8][CH:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:3][C:2]4([F:1])[F:16])[CH:41]=[C:42]([F:47])[CH:43]=3)[N:38]=2)[N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)(F)C1
Reactant: Fc1cc(F)c2nc(-c3nnc4ccccn34)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)C(F)(F)C1
Reaction time: 0.25 h

Procedure:
tert-Butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (0.0706 g, 0.298 mmol) was treated with 1 M KOtBu in THF (0.283 mL, 0.283 mmol) and stirred for 15 minutes. The solution was treated with 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6,8-difluoroquinoline (0.042 g, 0.149 mmol) and DMF (0.80 mL) then the mixture was stirred at ambient temperature for 16 hours. The mixture was directly chromatographed on SiO2 eluting with a gradient of 2% NH4OH in isopropanol/ethyl acetate. The desired product was collected and concentrated to a colorless oil, (72 mg). MS APCI (+) m/z 500.0 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: BrCc1cccnc1
Product: O=C(c1cn(Cc2cccnc2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 3-bromomethyl-pyridine gave the title compound.
Reaction SMILES: N[C:2]1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=1[S:30]([NH:33][C:34]1[CH:35]=[C:36](C)[CH:37]=[CH:38][CH:39]=1)(=[O:32])=[O:31]>>[NH2:27][C:25]1[CH:24]=[CH:23][C:22]([S:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH3:2])=[CH:36][CH:35]=2)(=[O:31])=[O:32])=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1cccc(C)c1
Product: COc1cc(N)ccc1S(=O)(=O)Nc1ccc(C)cc1
Yield: 93 %

Procedure:
(RK1-1-42) I This compound was prepared according to the procedure described for compound 12a except using 11i to obtain the required product as a light yellow solid (130 mg, 93%). Mp=158-160° C.; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.2 Hz, 2H), 6.93 (d, J=8.2 Hz, 2H) 6.70 (br s, 1H), 6.16 (s, 1H), 6.14 (app d, J=2.0 Hz, 1H), 4.05 (br s, 2H), 3.95 (s, 3H), 2.23 (s, 3H).