Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][C:4](O)=[O:5].Cl.C([N:19]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][C:4]([NH2:19])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCCCCCCC(O)CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCC(O)CC(N)=O
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 3-hydroxydodecanoic acid (0.26 g) in tetrahydrofuran (4 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g) and 1-hydroxybenzotriazole (0.24 g). After stirring for 30 minutes, 28% ammonium hydroxide (0.17 ml) was added and the mixture was stirred at room temperature overnight. Then, the mixture was diluted with ethyl acetate (100 ml) and washed with 0.1 N-hydrochloric acid (100 ml×2), saturated sodium bicarbonate (50 ml), and brine (50 ml). After drying over magnesium sulfate and evaporation, the residue was recrystallized from isopropyl alcohol (1 ml) to give 3-hydroxydodecanamide (0.20 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C([Li])CCC.CCCCCC.[Br:23]C1C(F)=C(F)C(F)=C(F)C=1F>O1CCCC1.O.C(OCC)(=O)C>[Br:23][C:10]1[N:5]2[N:4]=[C:3]([CH2:1][CH3:2])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: CCc1cc2ccccn2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of 2-ethylpyrazolo[1,5-a]pyridine (5.0 g, 34.2 mmol) in tetrahydrofuran (50 mL) was cooled to below −70° C. under a nitrogen stream, and then a solution of n-butyllithium in hexane (32.5 mL, 1.58M solution, 51.4 mmol) was added dropwise at below −60° C. After stirring for 1 hour, bromopentafluorobenzene (9.3 g, 37.7 mmol) was added dropwise to the reaction mixture at below −60° C. The reaction mixture was stirred for 2 hours at below −70° C., and then water (50 mL) was added to the reaction mixture and the temperature was raised to room temperature. Ethyl acetate (50 mL) and water (50 mL) were added thereto, and extraction was performed with ethyl acetate. The organic extract was washed twice with 5% brine (50 mL) and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to afford 6.9 g of the title compound.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17](OCC)=[O:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][CH2:17][OH:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC1CC(c2ccccc2)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CC(c2ccccc2)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
Ethyl 3-phenylindan-1-acetate (84.3 g, 0.3 mol) in THF (300 ml) was added dropwise with stirring to LiAlH4 (10 g) in THF (200 ml) under N2 and the mixture stirred at 80° C. overnight. Processing by standard conditions yielded 2-(3-phenylindan-1-yl)ethanol as an oil (47.3 g), IR 3100-3600 cm-1 (OH). This alcohol could also obtained by reduction of the ester in THF using LiBH4. The alcohol (43.15 g, 0.18 mol) was refluxed overnight with 48% HBr (280 ml), cooled, extracted with ether which, with standard processing, gave 2-(3-phenylindan-1-yl) ethyl bromide (50.8 g) as an oil. This bromo-compound (41.8 g, 0.14 mol) in Me2CO (160 ml) was added to a solution of NaCN (7 g, 0.143 mol) in H2O (40 ml) and the solution stirred and refluxed for 64 hours. The solution was evaporated to dryness and the product extracted with a mixture of AcOEt and H2O. After drying (Na2SO4), filtration and evaporation 3-(3-phenylindan-1-yl)propionitrile (26.8 g) was obtained as a solid, IR 2250 cm-1 (CN). This nitrile (24.3 g, 0.1 mol) in hot EtOCH2CH2OH (100 ml) was treated with NaOH (24.3 g, 0.6 mol) in H2O (40 ml) and the solution refluxed for 6 hours. It was then poured into conc. HCl (50 ml) in H2O (250 ml), extracted with Et2O and the Et2O extracted with 2N NaOH. Acidification gave the title compound. NMR (CCl4)δ1.5-3.3 (7H, CH2), 4.12 (1H, CH), 6.8-7.3 (9H,Ar), 11.92 (1H, exchangeable). cl EXAMPLE 3
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:17])[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)[CH3:2].[OH:18][NH2:19].O>CCO.CC(O)=O>[CH2:1]([O:3][C:4]1[C:5]2([OH:17])[CH:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:19][O:18]2)[CH2:7][CH2:8][CH:9]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=NOC2(O)C(OCC)=CCCC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate 5.0 g (20.73 mmol) in 20 mL of EtOH and 5 mL of AcOH, 1.3 mL (20.78 mmol) of HONH2.H2O (50% wt/wt) was added. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/Hexane:3/7) to afford 1.35 g (25% yield) as a white solid of ethyl 7-ethoxy-7a-hydroxy-3a,4,5,7a-tetrahydro-1,2-benzisoxazole-3-carboxylate
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([N:28]=[C:29]=[O:30])[CH2:26][CH3:27].CN(C1C=CC=CN=1)C>ClCCl>[Cl:1][C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([CH:14]([O:19][C:29](=[O:30])[NH:28][CH2:25][CH2:26][CH3:27])[C:15]([F:16])([F:17])[F:18])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(C(O)C(F)(F)F)c(C)c(Oc2c(C)cc(Cl)cc2C)n1
Reactant: CCCN=C=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCNC(=O)OC(c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C)C(F)(F)F

Procedure:
A mixture of 1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trifluoro-ethanol (21 mg, 0.0589 mmol), propyl isocyanate (0.1 ml), dimethylaminopyridine (20 mg) in dichloromethane (2 ml) was heated at reflux for 6 hrs. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give 23 mg of yellow solid. The solid was purified by preparative thin layer chromatography (run in 20% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:46]=3)[CH:41]=2)[N:34]=1.[CH2:59](O)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:37][CH:36]=[C:35]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:46]=3)[CH:41]=2)[N:34]=1
Reactant: CCCCCCCCO
Reactant: CCCCCCCCOc1ccc2cc(-c3ccc(O)c(F)n3)ccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc2cc(-c3ccc(OCCCCCCCC)c(F)n3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
1.06 g (6.11 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 1.60 g (6.11 mmol) of triphenylphosphine in 50 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 0.5 hour. 1.50 g (4.08 mmol) of 2-fluoro-3-hydroxy-6-(6-octyloxynaphth-2-yl)pyridine and 0.80 g (6.11 mmol) of 1-octanol are then added. After a reaction time of 1 hour at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 1.74 g of 2-fluoro-3-octyloxy-6-(6-octyloxynaphth-2-yl)pyridine. ##STR69##
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=2)[CH:3]=1.[OH:29]O>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=2)=[O:29])[CH:3]=1
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2cc(Cl)c3c(c2)COC(=O)N3)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cc(Cl)c3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 8-chloro-6-[4-(4-acetamido-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[CH3:10].Cl[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1>CN(C=O)C>[N:30]1([CH2:29][N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:15]2[CH2:16][CH2:17][CH2:18][N:14]2[S:11]([C:6]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([F:3])[CH:5]=2)(=[O:13])=[O:12])=[O:20])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1
Reactant: ClCn1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N2CCCC2C(=O)Nc2ccccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCC2C(=O)N(Cn2nnc3ccccc32)c2ccccc2)cc1F
Reaction time: 1 h
Yield: 76 %

Procedure:
Under inert atmosphere, to a stirred solution of NaH (5 mg, 0.13 mmol) in 0.20 ml anhydrous DMF at 0° C., was added a solution of parent compound 1-((3-fluoro-4-methylphenyl)sulfonyl)-N-phenylpyrrolidine-2-carboxamide (0.016 g, 0.04 mmol) in 0.20 ml anhydrous DMF. After 1 h at 0° C., a solution of 1-(chloromethyl)-1H-benzotriazole (0.022 g, 0.13 mmol) in 0.20 ml anhydrous DMF was added to the reaction mixture. This mixture was stirred for 16 h, and then solvent was completely removed. The crude was chromatographically purified over SiO2 using Hexane/AcOEt as the eluant, yielding 0.015 g (32%) of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][CH2:23][CH2:24][CH3:25])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][CH2:23][CH2:24][CH3:25])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)n1Cc1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.88 g, 1.64 mmol) was disolved in methylene chloride (16 mL) and trifluoroacetic acid (16 mL). After stirring for 3 hours the reaction mixture was evaporated in vacuo. Dilute NaHCO3 was added to adjust the pH to 6 and extracted with ethyl acetate. This extract was dried over MgSO4 and then evaporated in vacuo and purified via chromatograph (eluant methanol in chloroform).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC.CCOCC>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[O:16][CH2:15][CH2:14][O:6]1
Reactant: OCCO
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(CCCCl)OCCO2)cc1

Procedure:
This compound was synthesized as described under 5.a) with 20.0 g (101.6 mmol) of 4-chloro-1-(4-methylphenyl)-1-butanone (origin: Acros), 20 ml of ethylene glycol and ca. 1 g of p-toluenesulfonic acid in 120 ml of toluene to give 25.2 g (99%) of the crude compound, which was used for further functionalization. Column chromatography of 2 g (SiO2, heptane/ether 9:1) afforded 1.51 g of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:15]=1[NH2:16])[CH3:13]>>[CH2:12]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])[CH3:13]
Reactant: CCc1cccc(CC)c1N
Reactant: O=C(O)Cc1ccccc1Br
Product: CCc1cccc(CC)c1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,6-diethylaniline to yield 2-[(2,6-diethylphenyl)amino]phenylacetic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:31][CH3:32])=[C:25]([S:27](Cl)(=O)=O)[CH:26]=1>C1COCC1.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:31][CH3:32])=[C:25]([SH:27])[CH:26]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenylphosphine (11.4 g) was added portionwise to a stirred solution of 5-chloro-2-methoxybenzenesulphonyl chloride (3.0 g) in THF (30 ml). Water (4 ml) was added and the mixture stirred at RT for 2 h, after which the reaction was diluted with water (25 ml) then 2M sodium hydroxide solution and washed with ether. The aqueous layer was acidified with 2M hydrochloric acid and extracted with ethylacetate. The organic layer was dried and evaporated under reduced pressure, yield 3.1 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](=O)[C:13]([OH:15])=[O:14])=[CH:2]1.[NH2:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19].C([BH3-])#N.[Na+]>>[C:13]([CH:12]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19])[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)([OH:15])=[O:14]
Reactant: O=C(O)C(=O)CCc1c[nH]c2ccccc12
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1c[nH]c2ccccc12)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in example 24, 4-(3-indolyl)-2-oxobutyric acid and L-alanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-[1-carboxy-3-(3-indolyl)propyl]L-alanyl-L-proline. The mass spectrum of the trisilyated material shows a molecular ion at 603 m/e and a M+ -15 peak at 588 m/e.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[NH:23][N:24]=[N:25][C:21]=2[CH:20]=1>>[N:23]1[C:22]2[CH:26]=[CH:27][C:19]([NH:18][CH:4]=[C:5]3[C:16]4[C:8](=[CH:9][CH:10]=[C:11]5[C:15]=4[S:14][CH:13]=[N:12]5)[NH:7][C:6]3=[O:17])=[CH:20][C:21]=2[NH:25][N:24]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc2nn[nH]c2c1
Yield: 54 %

Procedure:
The title compound was prepared in 54% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 5-aminobenzotriazole according to Procedure J: 1H NMR (DMSO-d6): δ 11.18 (d, 1H), 10.9 (s, 1H), 9.23 (s, 1H), 8.12 (d, 1H), 7.96 (s, 1H), 7.78 (d, 1H), 7.48 (s, 1H), 7.1 (d, 1H); APCI-MS m/z 333 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@H:4]([CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[NH:5][C:6](=[O:35])[CH:7]([C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)[CH:8]([OH:25])[C:9]1[N:10]=[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:13]=1.Cl>[OH-].[Na+].CO.C(OCC)(=O)C>[OH:25][CH:8]([C:9]1[N:10]=[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])[N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH:13]=1)[CH:7]([C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)[C:6]([NH:5][C@H:4]([C:3]([OH:46])=[O:2])[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)=[O:35]
Reactant: CCCCc1nc(C(O)C(C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)OC)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1nc(C(O)C(C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C

Procedure:
A solution of N-[(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionyl]-L-tryptophan methyl ester (118 mg) in 1N aqueous sodium hydroxide solution (1.0 ml) and methanol (5.0 ml) was stirred at ambient temperature for 2 hours. The solution was acidified with 1N hydrochloric acid and the mixture was diluted with ethyl acetate followed by washing with brine. The organic layer was dried and evaporated to afford crude N-[(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionyl]-L-tryptophan.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.Cl.[CH3:12][NH:13][C@@H:14]([CH2:19][CH2:20][CH:21]=[CH2:22])[C:15]([O:17][CH3:18])=[O:16]>>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:13]([C@@H:14]([CH2:19][CH2:20][CH:21]=[CH2:22])[C:15]([O:17][CH3:18])=[O:16])[CH3:12])=[O:8]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: C=CCC[C@H](NC)C(=O)OC
Agent: Cl
Product: C=CCC[C@@H](C(=O)OC)N(C)C(=O)CCCC(F)(F)F
Yield: 65 %

Procedure:
Step L (1): 5,5,5-Trifluoropentanoic acid and (S)-methyl 2-(methylamino)hex-5-enoate hydrochloride from Step K (2) were coupled according to the conditions described in Step A (1). The crude reaction products were purified by silica-gel column chromatography to give 276 mg (65% yield) of (S)-methyl 2-(5,5,5-trifluoro-N-methylpentanamido)hex-5-enoate. LC-MS (M+H)+=296.3; 1H NMR (500 MHz, CDCl3) δ ppm 1.73-1.83 (m, 1H) 1.84-2.25 (m, 7H) 2.37-2.52 (m, 2H) 2.78-2.96 (m, 3H) 3.66-3.75 (m, 3H) 4.94-5.09 (m, 2H) 5.17 (dd, J=10.53, 4.73 Hz, 1H) 5.70-5.84 (m, J=6.71 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([F:20])[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:27]([CH2:29][C:30]#[N:31])=[O:28])N=C(C)C=1.C(N(CC)C(C)C)(C)C.O1CCOCC1>O>[F:20][C:2]1([F:1])[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[N:4]([C:27](=[O:28])[CH2:29][C:30]#[N:31])[CH2:3]1
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Reactant: FC1(F)CNC12CCCN(c1ncnc3[nH]ccc13)C2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CCC(=O)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
An optically-active compound of 4-(3,3-difluoro-1,6-diaza-spiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (6.6 g) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (7.7 g), N,N-diisopropylethylamine (4.3 ml) and 1,4-dioxane (132 ml), and the mixture was stirred at 100° C. for 2 hours. The mixture was cooled to room temperature. Then, thereto was added water, and the mixture was extracted with ethyl acetate. The separated aqueous layer was further extracted with ethyl acetate 5 times. The combined organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=3/2 to 2/3). To the resulting residue was added n-heptane, and the mixture was concentrated under reduced pressure. To the resulting residue was added diethylether, and the mixture was slurry-washed and filtered to give a solid (7.5 g). The filtrate was concentrated under reduced pressure. To the resulting residue was added diethylether, and the mixture was slurry-washed to give a solid (0.2 g). The combined solid was purified by silica gel column chromatography (eluent: chloroform/methanol=97/3 to 9/1). To the resulting solid was added ethanol, and the mixture was concentrated under reduced pressure to give the titled compound (7.1 g).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][N:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[O:16]1[CH2:22][CH2:21][CH2:20][O:19][C:18]2[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:17]1=2.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:16]1[CH2:22][CH2:21][CH2:20][O:19][C:18]2[CH:23]=[C:24]([C:2]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][N:4]4[CH2:13][CH2:14][CH2:15][C:3]=34)[CH:25]=[CH:26][C:17]1=2
Reactant: Brc1c(-c2ccccn2)nn2c1CCC2
Reactant: OB(O)c1ccc2c(c1)OCCCO2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2ccc4c(c2)OCCCO4)CCC3)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.8 %

Procedure:
Add bis(1,2-bis(diphenylphosphino)ethane)palladium(0) (Pd(DIPHOS)2; 0.086 g, 0.095 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (Pd2(dba)3); 0.088 g, 0.095 mmol) to a degassed solution of 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 4, 0.25 g, 0.95 mmol) in THF (2.5 mL). Purge the reaction mixture with nitrogen for 2 min and stir for 20 min at room temperature. Add 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (158 mg, 0.95 mmol) in DMF (1 mL). After stirring the reaction mixture for 10 min, add 2M aqueous potassium carbonate solution (1.2 mL). Heat the solution at 65° C. for 1 h. Add Pd2(dba)3 (0.088 g, 0.095 mmol) twice after 1 h and again after 2 h. Continue stirring the reaction mixture for 15 h at 65° C. Cool the mixture to room temperature, filter through a Celite® pad, and wash the celite pad with dichloromethane (50 mL) and methanol (50 mL). Evaporate the filtrate. Purification of the residue by flash chromatography (SiO2, 1:3 [88:8:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane) gives the title compound (69 mg, 22%) as a brown oil.