Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(C(C)C)C=C(C(C)C)C=1S(O[CH2:20][C:21]1([OH:41])[CH2:24][N:23]([C:25]([C:27]2[C:31]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=3[F:40])=[CH:30][S:29][CH:28]=2)=[O:26])[CH2:22]1)(=O)=O)C.[H-].[Na+].[C:44]([NH2:48])([CH3:47])([CH3:46])[CH3:45]>O1CCCC1>[CH3:45][C:44]([NH:48][CH2:20][C:21]1([OH:41])[CH2:24][N:23]([C:25]([C:27]2[C:31]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=3[F:40])=[CH:30][S:29][CH:28]=2)=[O:26])[CH2:22]1)([CH3:47])[CH3:46]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)OCC2(O)CN(C(=O)c3cscc3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Reactant: CC(C)(C)N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NCC1(O)CN(C(=O)c2cscc2Nc2ccc(I)cc2F)C1
Reaction time: 16 h
Yield: 11 %

Procedure:
[1-({4-[(2-Fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl 2,4,6-tris(1-methylethyl)benzenesulfonate (101 mg, 0.141 mmol) was dissolved in tetrahydrofuran (2 mL) and was treated with sodium hydride (60 wt % dispersion in oil; 17 mg, 0.425 mmol) at ambient for 20 minutes. Tetrahydrofuran (2 mL) and tert-butylamine (0.1 mL) were added and the mixture was stirred at ambient for 16 h. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC and the clean fractions were combined, neutralized with saturated sodium bicarbonate solution and the organic solvent was removed in vacuo. The remaining aqueous residue was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-{[(1,1-dimethylethyl)amino]methyl}-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol (8 mg, 0.016 mmol, 11% yield): 1H NMR (400 MHz, d6-DMSO): 9.64 (br, 1H), 8.08 (d, 1H), 7.59 (dd, 1H), 7.44 (dd, 1H), 7.36 (t, 1H), 7.12 (d, 1H), 4.39 (d, 1H), 4.22 (d, 1H), 4.03 (d, 1H), 3.80 (d, 1H), 2.68 (br, 2H) 1.04 (s, 9H); MS (EI) for C19H23FIN3O2S: 504 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([CH3:12])=[CH:4][N:3]=1.[OH-].[NH4+:14]>>[NH2:1][C:2]1[C:7]([S:8]([NH2:14])(=[O:10])=[O:9])=[CH:6][C:5]([CH3:12])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)c(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cnc(N)c(S(N)(=O)=O)c1

Procedure:
The product of Example 104A was reacted with concentrated ammonium hydroxide at ambient temperature overnight. The reaction mixture was concentrated to give the title compound as a light yellow solid in quantitative yield. MS (DCI/NH3) m/z 188 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 2.17 (m, 3H), 6.28 (s, 2H), 7.43 (s, 2H), 7.70 (d, J=1.84 Hz, 1H), 8.00 (d, J=2.21 Hz, 1H).
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:17])(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([S:13][Cl:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCCCCCCS
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCSCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of dodecane thiol (1.00 mL, 4.17 mmol, Aldrich Chemical Company) in 20 mL CHCl3 was added sulfuryl chloride (0.74 mL, 9.18 mmol, Aldrich Chemical Company), and the resulting mixture was stirred at room temperature for 18 h. Removal of solvent (aspirator), afforded dodecansulfenyl chloride that was determined to be sufficiently pure by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:20][C:15]3[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]2=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(c1ccc(Cl)cc1)N1Cc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-chlorophenyl)-ethylamine (117 mg (0.75 mmol), 2-bromomethyl-benzoic acid methyl ester (172 mg, 0.75 mmol), and K2CO3 (207 mg, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using a gradient of hexanes to ethyl acetate afforded 38 mg of 2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydroisoindol-1-one, as the racemic mixture. Chromatography (HPLC) of this material through ChrialCel OD (250×20 mm i.d., 10 μm) using 5% isopropanol in hexanes afforded 11.6 mg of R-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydro-isoindol-1-one and 8.3 mg of S-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydro-isoindol-1-one. GC/MS for S-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydroisoindol-1-one gave: m/z (rel.int.) 274 (M+, 9), 272 (M+, 56), 258 (26), 256 (57), 160 (20), 138 (32), 119 (100), 103 (50), 91 (65), and 77 (61).
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd]>[C:5]1([CH2:6][CH2:7][CH2:8][CH2:3][CH:2]=[CH:1][C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH:4]=[CH:3][CH:2]=[CH:1][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CCc1ccccc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=CCCCCc1ccccc1
Yield: 97 %

Procedure:
(S)-2-phenethyl-N-Boc-pyrrolidine (44 a) (PAA 2-28). A 10-mL round-bottom flask fitted with a 3-way tap and balloon was charged with 160 mg of 10% Pd—C. The flask was evacuated and filled with hydrogen gas 10 times. EtOH (5 mL) was added via syringe and stirred for several minutes. Alkene 45 a (260 mg,) in 2 mL EtOH was added via syringe and stirred for 24 h. Hydrogen gas was added as the balloon deflated. Upon complete reaction the catalyst was removed by filtration. The product was concentrated in vacuo to yield 251 mg (97%) of colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.19-7.30 (m, 5H), 3.76-3.88 (br m, 1H), 3.34-3.43 (br m, 2H), 2.59-2.62 (m, 2H), 1.62-2.16 (m, 6H), 1.46 (s, 9H).
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([CH3:12])=[C:5]([CH3:13])[C:4]=1[O:14][CH3:15].[C:16]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>O1CCCC1>[CH3:15][O:14][C:4]1[C:5]([CH3:13])=[C:6]([CH3:12])[C:7]([O:10][CH3:11])=[C:8]([CH3:9])[C:3]=1[C:16]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)([OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: CCCCCCC(=O)c1cccnc1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(O)(c1cccnc1)c1c(C)c(OC)c(C)c(C)c1OC
Yield: 39.3 %

Procedure:
A Grignard reagent was prepared from 693 mg (28.3 g atom) of magnesium, 7.6 g (29.3 mmol) of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene and tetrahydrofuran at 65° C. and cooled to 0° C., to which a solution of 3.75 g (21.9 mmol) of 3-heptanoylpyridine in 10 ml of tetrahydrofuran was added dropwise. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour, to which water was added and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified with silica gel column chromatography (isopropyl ether) and recrystallized from hexane, to give 3.2 g (39%) of 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)heptanol. m.p. 109°-110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([N:9]=[C:10]([O:12][CH2:13]C)[CH3:11])=C[O-])=[O:5])[CH3:2].[K+].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:9]=[C:10]([CH3:11])[O:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=C[O-])N=C(C)OCC
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1coc(C)n1
Temperature: 110 °C
Yield: 44.9 %

Procedure:
5 g (25 mmol) of potassium 2-ethoxycarbonyl-2-(1-ethoxy-ethylideneamino)-ethenolate were completely dissolved in 15 mL acetic acid at RT, and then the solution was heated to 110° C. overnight. After cooling down, 100 mL EtOAc were added and the solution is neutralized with saturated NaHCO3 solution. The organic phase was separated, dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 1:2) yielded 1.74 g (45%) of 2-methyl-oxazole-4-carboxylic acid ethyl ester as an yellow oil, MS: 156 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10](I)[C:3]=12.[CH3:13][N:14]1[CH2:19][CH2:18][O:17][C:16]2[CH:20]=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][C:15]1=2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10]([C:22]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][CH2:19][N:14]([CH3:13])[C:15]=4[CH:23]=3)[C:3]=12
Reactant: Cn1cc(I)c2c(Br)ccnc21
Reactant: CN1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: CN1CCOc2ccc(-c3cn(C)c4nccc(Br)c34)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Alternatively, to a mixture of 4-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (D7) (1 g, 2.97 mmol), 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.857 g, 3.12 mmol) in DME (18 mL) and MeOH (2.0 mL) was added bis(triphenylphosphine)palladium(II) chloride (0.208 g, 0.297 mmol) and 2M sodium carbonate aq. solution (14.84 mL, 29.7 mmol). The mixture was stirred at 60° C. for 1 hour. The mixture was cooled to RT and filtered. The solid was washed with excess ethyl acetate and the filtrate concentrated in vacuo. The residue aqueous was extracted with ethyl acetate (4×200 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified on normal phase chromatography eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give the title compound (344 mg). LCMS (A): m/z (M+H)+ 358/360, C17H16BrN3O requires 357/359 (acidic).
Reaction SMILES: P([O-])([O-])([O-])=O.N[C@H](C(O)=O)C[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1>>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: c1ccc2[nH]ccc2c1

Procedure:
0.1 ml of the aforesaid treated cell suspension was added to 25 ml of a reaction solution which contained per ml thereof, 100μmole of phosphate buffer (pH 8.0), 5 μmole of L-tryptophan and 0.04μmole of pyridoxalphosphoric acid, and reacted at 37° C. for 15 minutes. The amount of indole formed was determined by a conventional method [O. H. Smith and C. Janofsky: "Methods in Enzymology", Academic, New York, (1962, vol. 5, pages 794-806)].
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:15][O:14][C:12]1[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[C:4]([CH:13]=1)[C:3]([OH:16])=[O:2]
Reactant: COC(=O)c1cc(OC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 114.8 %

Procedure:
A solution of dimethyl-5-methoxy-isophthalate (2.5 g, 11.1 mmol) in tetrahydrofuran/methanol (56 mL/20 mL) was treated with 2.0 N sodium hydroxide (12 mL, 25 mmol). The reaction was left stirring for 15 hours at room temperature. After the solution was concentrated, the solid was dissolved in water and acidified with 2.0 N hydrogen chloride. Ethyl acetate was used to extract the precipitate, which was then washed with brine and dried over anhydrous sodium sulphate. After removal of solvent in vacuo, a total of 2.5 g (quantitative) of 5-methoxyisophthalic acid was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[C:17]3[C:22]([F:25])([F:24])[F:23])(=[O:10])=[O:9])=[C:4]([N+:26]([O-])=O)[CH:3]=1.Cl[Sn]Cl>Cl.CCO>[NH2:26][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[C:22]([F:24])([F:25])[F:23])(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Yield: 100.7 %

Procedure:
In a similar fashion using route 1 general procedure 4, 4-chloro-2-nitro-N-(4-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 252) (365 mg, 0.84 mmol), SnCl2 (637 mg, 3.37 mmol), 6N HCl (2 drops) and EtOH (15 ml) gave the title compound (340 mg, 100%).
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[Cl:7][C:8]1[CH:9]=[C:10]([N:16]=[C:17]=[O:18])[CH:11]=[CH:12][C:13]=1[C:14]#[N:15]>CC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:5][C:3](=[NH:6])[CH3:4])=[O:18])[CH:11]=[CH:12][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(N=C=O)cc1Cl
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(=N)NC(=O)Nc1ccc(C#N)c(Cl)c1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.06 g. sodium in 250 ml. dry acetone, 9.2 g. acetamidine hydrochloride and 16 g. 3-chloro-4-cyanophenyl isocyanate in 250 ml. dry acetone, there was obtained after filtration of the reaction mixture a solid which on washing with water and recrystallization from methyl alcohol gave 1-(3-chloro-4-cyanophenyl)3 -(acetimidoyl)urea; m.p.182°-183°C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[S:18])[NH2:17])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.Br[CH2:24][C:25]([C:27]1[CH2:31][C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1)=O>C(O)C.O>[C:32]1([C@@H:30]2[O:29][N:28]=[C:27]([C:25]3[N:17]=[C:16]([CH:13]4[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]5[C:2]([CH3:1])=[CH:3][C:4]([C:19]([F:22])([F:20])[F:21])=[N:5]5)[CH2:11][CH2:12]4)[S:18][CH:24]=3)[CH2:31]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)C1=NO[C@@H](c2ccccc2)C1
Solvent: CCO
Solvent: O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NO[C@@H](c4ccccc4)C3)cs2)CC1
Temperature: 50 °C

Procedure:
A mixture of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidine-carbothioamide (i.e. the product of Example 8, Step C) (1.7 g, 5.0 mmol) and 2-bromo-1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]ethanone (i.e. the product of Example 12, Step E) (1.35 g, 5 mmol) in ethanol (15 mL) was heated at 50° C. for 30 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give the title product as a pale-yellow gum. High performance liquid chromatography (HPLC) analysis showed that the title product was about 95% pure and contained the (R)-enantiomer in about 98% enantiomeric excess.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1[N:5]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH3:19])[C:14]=2[C:15]([O:17]C)=[O:16])[S:7][C:8]=1[CH3:9]>CO>[CH3:3][C:4]1[N:5]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH3:19])[C:14]=2[C:15]([O-:17])=[O:16])[S:7][C:8]=1[CH3:9].[Na+:2]
Reactant: COC(=O)c1c(-c2nc(C)c(C)s2)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2cnn(C)c2C(=O)[O-])sc1C

Procedure:
An aqueous solution (1 ml) of sodium hydroxide (9.6 mg) was added to a methanol (1 ml) solution of the methyl 4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (30 mg) obtained in (Example 2.2) <Step 1>, and the obtained mixture was then heated to reflux for 15 minutes. Thereafter, the solvent was distilled away under reduced pressure, and the residue was then subjected to azeotropy with toluene, so as to obtain a crude product of the title compound.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:11]([OH:46])[CH2:12][N:13]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35]C(OCC1C=CC=CC=1)=O)[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:54]>[Pd].C(O)C>[ClH:54].[NH2:35][CH2:34][CH2:33][CH2:32][CH2:31][N:13]([CH2:12][CH:11]([OH:46])[CH:10]([NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15]
Reactant: O=C(NCCCCN(CC(O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCCCN(CC(O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 24 h

Procedure:
The ester product from part (g) is taken into 40 ml. of 95% ethanol, 0.584 ml. of 1N hydrochloric acid, and 50 mg. of palladium on carbon catalyst (10%). The mixture is stirred under hydrogen pressure for 24 hours. The reaction mixture is then filtered and concentrated to dryness in vacuo. The crude product is purified on an LH-20 column in water to yield 1-[[(4-aminobutyl)[3-(benzoylamino)-2-hydroxy-4-phenylbutyl]amino]carbonyl]-L-proline, monohydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][C:3]=1[CH3:12]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(C#CCO)ccc1Cl
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(CCCO)ccc1Cl
Temperature: 65 °C
Reaction time: 11 h
Yield: 79.1 %

Procedure:
A suspension of Compound 67-1 (3.08 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (70 ml) was stirred under a hydrogen atmosphere at 65° C. for 11 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-75:25) to give the object product (2.49 g) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:14][CH:15](O)[C:16]#[CH:17].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[I:14][CH:15]([O:12][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]#[CH:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C#CC(O)I
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CC(I)OC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a magnetically stirred solution of N-t-butoxycarbonyl-L-alanine (5.00 g., 0.026 mole) and iodopropargyl alcohol (4.81 g., 0.026 mole) in anhydrous dichloromethane (100 ml.) cooled to 0° C. with an ice-bath was added 4-dimethylaminopyridine (0.32 g., 0.0026 mole) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.57 g., 0.029 mole). The reaction mixture continued to stir at 0° C. for one hour, and was then stored in a refrigerator at 5° C. overnight. The reaction mixture was transferred to a separatory funnel and diluted to double volume (200 ml.) with dichloromethane, then washed successively with 100 ml. of water, 3×100 ml. of 10% aqueous potassium hydrogen sulfate, 100 ml. of water, 3×100 ml. of saturated aqueous sodium bicarbonate, 3×100 ml. of water and a final wash with 100 ml. of saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo with a rotary evaporator to a clear colorless oil which crystallized on standing. A quantitative yield (9.34 g.) of N-t-butoxycarbonyl-L-alanine iodopropargyl ester was obtained. m.p.=71°-73° C. 1H-NMR (200 MHz, DMSOd6) δ=1.25 ppm, d, 3H; 1.40, s, 9H; 4.01, m, 1H; 4.85, s, 2H; 7.33, d, 1H. IR (CHCl3) 1170, 1375, 1400, 1715, 1750, 2205 cm-1.
Reaction SMILES: CO.[N+:3]([C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:9]=[C:8]([C:17]([NH:19][C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:22]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:21]=2)=[O:18])[CH:7]=1)([O-])=O>C1COCC1.[Pd]>[NH2:3][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:9]=[C:8]([C:17]([NH:19][C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:22]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:21]=2)=[O:18])[CH:7]=1
Reactant: Cc1ccc(-c2cc(NC(=O)c3cc([N+](=O)[O-])n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2cc(NC(=O)c3cc(N)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Reaction time: 16 h
Yield: 99.3 %

Procedure:
Methanol (5 mL) and Pd/C were added to a solution of 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxamide (183 mg, 0.38 mmol) in THF. The flask was then evacuated and filled with hydrogen. The reaction mixture was stirred for 16 hrs. The catalyst was filtered on celite and the solution was concentrated and dried to give 5-amino-1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxamide (170 mg, quantitative).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([CH3:10])=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][N:12]([CH:14](N(C)C)OC(C)(C)C)[CH3:13]>CN(C)C=O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([CH:10]=[CH:11][N:12]([CH3:14])[CH3:13])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ncc([N+](=O)[O-])n1C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ncc([N+](=O)[O-])n1C

Procedure:
14.1 g. (0.1 mole) of 5-nitro-1,2-dimethylimidazole and 21 g. (0.12 mole) of bis-dimethylamino-tert.-butoxymethane were heated in 90 ml. of dimethylformamide to 130° C. for 15 minutes. After cooling, the red crystals were vacuum-filtered and recrystallized from dimethylformamide.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:11][CH2:12][CH3:13]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:17]=[CH:16]/[C:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])=[O:18])=[CH:3][CH:4]=1)#[N:7]
Reactant: C=CC(=O)OCCCC
Reactant: N#Cc1ccc(I)cc1
Product: CCCCOC(=O)/C=C/c1ccc(C#N)cc1

Procedure:
4-Iodobenzonitrile (57 mg, 0.25 mmol) and n-butylacrylate (54 μL, 0.375 mmol) were coupled using the procedure described above, except the reaction was performed at 50° C., to give 100% conversion to (E)-n-butyl 3-(4-cyanophenyl)acrylate by GC analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][CH3:19])[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-])=O.CO.[H][H]>[Pd].C(OCC)(=O)C>[CH2:17]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([NH2:1])[CH:5]=2)[CH2:18][CH3:19]
Reactant: [H][H]
Reactant: CCCn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCn1c2c(c3cc(N)ccc31)CCCC2
Yield: 95.8 %

Procedure:
A solution of the compound obtained in Step 1 (270 mg, 1.05 mmol) and 10% palladium on carbon (50% wet, 10 mg, 0.09 mmol) in a mixed solvent of methanol (4 mL) and ethyl acetate (4 mL) was stirred at room temperature for 14 hr under 1 atm of hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 9-propyl-2,3,4,9-tetrahydro-1H-carbazol-6-amine (230 mg, 1.006 mmol, 96%) as a brown oil.