Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:23][C:22]2[S:24][C:25](Br)=[CH:26][C:21]=2[CH:20]=1)=[O:18])[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].O>O1CCCC1.[Cu]I.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>[CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:23][C:22]2[S:24][C:25]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])=[CH:26][C:21]=2[CH:20]=1)=[O:18])[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1)c1cc2cc(Br)sc2[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: C[Si](C)(C)C#Cc1cc2cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)[nH]c2s1
Reaction time: 8 h
Yield: 4 %

Procedure:
Using a modified procedure of J. M. Tour et al. (J. Org. Chem., 61: 6906-6921 (1996)), to a degassed solution of 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide (106 mg, 0.24 mmol) in tetrahydrofuran (5 ml) was sequentially added diisopropylamine (36 μl, 0.26 mmol), a mixture of copper(I) iodide (9 mg, 0.05 mmol) and dichlorobis(triphenylphosphine)palladium(II) (68 mg, 0.1 mmol), and (trimethylsilyl)acetylene (41 μl, 0.29 mmol). The mixture was stirred overnight, poured into water, and extracted with dichloromethane. The combined organic phases were washed with saturated NaCl, dried over MgSO4, and concentrated. The product was purified by Chromatotron-chromatography (dichloromethane; 20:1 dichloromethane:methanol) to give the title product (4.5 mg, 4%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.[OH-].[Ca+2].[OH-].[C:17](CC(Cl)=O)([CH3:20])([CH3:19])[CH3:18]>Cl>[C:17]([C:6]1[C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:3][C:2]=1[CH3:1])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Product: Cc1[nH]n(-c2ccccc2)c(=O)c1C(C)(C)C
Reaction time: 8 h

Procedure:
3-Methyl-1-phenylpyrazol-5-one (5 g; 0.029 mole) was placed in a flask equipped with a stirrer and reflux condenser. Dry and distilled dioxane (40 ml) was added by warming and to the clear solution calcium hydroxide (6.4 g; 0.086 mole) was added followed by drop wise addition of tert-butylacetyl chloride (4.8 ml; 0.034 mole). The mixture was heated to reflux for 4 hours and then poured into 2M HCl (200 ml) to decompose the calcium complex. A light brown precipitate formed immediately, which was filtered off under suction after refrigerating overnight. The product washed with water and dried under vacuum at 50° C. The product was recrystallised from methanol to give an off-white crystalline solid, m.p 85-86° C.; 6.8 g (82%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].Cl[CH2:15]I.C([Zn][CH2:20][CH3:21])C.[NH4+].[Cl-].[NH4+].[OH-]>ClCCCl.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:20]([CH3:21])[CH3:15])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CC[Zn]CC
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: ClCI
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Compound 3 (5.56 g, 24.0 mmol) was added to a solution of chloroiodomethane (5.59 mL, 76.8 mmol) in 1,2-dichloroethane (35 mL) under an atmosphere of nitrogen. The solution was cooled to 0° C. with an ice bath and diethyl zinc (38.4 mL, 1.0 M in hexanes, 38.4 mmol) was added over 10 minutes. The resulting mixture was stirred for 30 minutes and allowed to warm to room temperature. It was again cooled to 0° C. with an ice bath, and saturated aqueous NH4Cl (150 mL) was added, followed by concentrated aqueous NH4OH (25 mL) and EtOAc (200 mL). The layers were separated and the aqueous phase was extracted with additional EtOAc (2×100 mL). The organic phases were combined, dried (Na2SO4) and concentrated to a crude oil which was purified over silica gel (100% hexanes) to yield compound 4 (1.76 g, 7.2 mmol, 30% yield) as a colorless oil which was characterized using 1H NMR.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C@@H:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:14]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].[ClH:34].C(OCC)(=O)C>C(O)C.C(Cl)Cl>[ClH:34].[C:21]1([C@H:19]([NH:18][C@H:15]2[CH2:16][CH2:17][C@@H:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:12][CH:11]=3)[CH2:14]2)[CH3:20])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCC(=O)O)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
{4-[(1R,3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}cyclopentyl]phenoxy}acetic acid ethyl ester (720 mg, 1.7 mmol) was dissolved in ethanol (5 mL), followed by addition of 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred for 1 hour at room temperature. 1N hydrochloric acid was added dropwise to the reaction mixture to make the reaction solution acidic, and then the solvent was distilled off under reduced pressure. The aqueous phase was extracted with methylene chloride, the extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was dissolved in methylene chloride (6 mL), followed by addition of an ethyl acetate solution of 1N hydrochloric acid (2 mL), and then the solvent was distilled off under reduced pressure. Ethyl acetate and hexane were added to the residue, followed by treatment with ultrasonic waves, and then the solid matter generated was collected by filtration to give the title compound (237 mg, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:17])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(Cl)Cl.C(O)(=O)C>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=3)[C:7](=[O:17])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1C(=O)N(c2ccccc2)c2cc(O)ccc21
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccc(O)cc2N1c1ccccc1
Temperature: 140 °C
Yield: 17 %

Procedure:
A mixture of 6-hydroxy-1-phenyl-1H-indole-2,3-dione (13 mg, 0.054 mmol) and 3-(trifluoromethyl)aniline (160 mg, 1 mmol) in CH2Cl2 (1 mL) and acetic acid (1 drop) was heated at 140° C. The crude product was purified preparative TLC [Eluent: EtOAc/hexane (2:3)], giving the desired product (3.5 mg, 17%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.CO.C1COCC1.CO.[CH3:37][N:38]([CH3:48])[CH2:39][C:40]1[N:41]=[C:42]([N+:45]([O-])=O)[NH:43][CH:44]=1>[Ni].C(Cl)Cl.CO>[CH3:37][N:38]([CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:5])[NH:43][CH:44]=1)[CH3:48]
Reactant: CN(C)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 485.1 [M+H]+; tR=3.24 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:28])=O>C1COCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:28])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cccc1C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cccc1C(=O)Cl
Reaction time: 4 h

Procedure:
To a solution of 2-methoxy-(N-t-butyloxycarbonyl-4-piperidyloxy)benzoic acid (3.2 g; 9.1 mmol) from Step 3 above in THF was added thionyl chloride (1 mL; 13.7 mmol) and pyridine (2 drops) while under a nitrogen atmosphere. The solution was stirred for 4 hours and then concentrated under reduced pressure to dryness. The residue was suspended in ether and filtered, and the filtrate was concentrated to dryness to yield 2-methoxy-(N-t-butyloxycarbonyl-4-piperidyloxy)benzoyl chloride.
Reaction SMILES: [Br-].[C:2]1(=[O:29])[N:6]([CH2:7]CC[N+](CCCNC(OC(C)(C)C)=O)(C)C)[C:5](=[O:24])[C:4]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:3]12.[CH3:30][NH2:31]>>[CH3:30][NH:31][C:5](=[O:24])[C:4]1[C:3](=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]([NH:6][CH3:7])=[O:29]
Reactant: CN
Reactant: CC(C)(C)OC(=O)NCCC[N+](C)(C)CCCN1C(=O)c2ccccc2C1=O
Agent: [Br-]
Product: CNC(=O)c1ccccc1C(=O)NC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(phthalimidopropyl)-N-((t-butoxycarbonylamino)propyl)-N,N-dimethylammonium bromide [1.6] (4.1 g, 0.87 mmol) was dissolved in ethanolic methylamine (33 wt %, 8.02M, 10 ml). The colourless solution was stirred at room temperature for 3 days, during which time a thick white precipitate formed (N,N′-dimethylphthalamide). The mixture was filtered; the solid was washed with a little cold ethanol. The filtrate was evaporated under reduced pressure to give an oil; this was triturated with ether and dried under high vacuum to give the title compound [1.7] as a foam. Used without further purffication.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br.[Br:15][CH2:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=O>>[BrH:15].[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:16]=2)[CH:20]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Product: COC(=O)c1ccc(-c2nc(-c3cccnc3)cs2)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 3-bromoacetylpyridine hydrobromide to obtain methyl 4-[4-(3-pyridyl)-2-thiazolyl]benzoate hydrobromide. The product was recrystallized from ethanol. Yield: 80%. Pale yellow prisms. Melting point: 241 to 242° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][C:19]1([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1>CCCCO>[NH2:25][C:19]1([CH3:18])[CH2:24][CH2:23][CH2:22][N:21]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[C:4]=23)[CH2:20]1.[Br:1][C:2]1[C:3]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:18])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCNC1
Reactant: COCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Product: COCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCCC(C)(N)C3)c12
Product: COCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCCC(C)(NC(=O)OC(C)(C)C)C3)c12
Yield: 49 %
Yield: 19 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (100 mg, 0.331 mmol, Example 31, Step A) and tert-butyl 3-methylpiperidin-3-ylcarbamate (213 mg, 0.993 mmol) in n-BuOH (4 mL) were heated to 160° C. for 48 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield N-(4-(3-amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (65 mg, 49% yield) as a solid and tert-butyl 1-(5-bromo-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylpiperidin-3-ylcarbamate (32 mg, 19% yield) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:21]3[C:22]4[C:27]([O:28][C:29](=[O:30])[C:20]=3[N:19]3[C:10]=2[C:11]2[C:16]([CH2:17][CH2:18]3)=[C:15]([O:34][CH3:35])[C:14]([O:36][CH3:37])=[C:13]([O:38][CH3:39])[CH:12]=2)=[CH:26][C:25]([OH:31])=[C:24]([O:32][CH3:33])[CH:23]=4)=[CH:5][C:4]=1[OH:40]>C(OC(=O)C)(=O)C.N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:4][C:3]([O:40][C:4]1[CH:5]=[C:6]([C:9]2[C:21]3[C:22]4[C:27]([O:28][C:29](=[O:30])[C:20]=3[N:19]3[C:10]=2[C:11]2[C:16]([CH2:17][CH2:18]3)=[C:15]([O:34][CH3:35])[C:14]([O:36][CH3:37])=[C:13]([O:38][CH3:39])[CH:12]=2)=[CH:26][C:25]([O:31][C:27]([CH3:26])=[O:28])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:2]
Reactant: COc1ccc(-c2c3n(c4c(=O)oc5cc(O)c(OC)cc5c24)CCc2c-3cc(OC)c(OC)c2OC)cc1O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(-c2c3n(c4c(=O)oc5cc(OC(C)=O)c(OC)cc5c24)CCc2c-3cc(OC)c(OC)c2OC)cc1OC(C)=O
Temperature: 18 °C
Reaction time: 26 h
Yield: 169.7 %

Procedure:
Lamellarin T (48 mg, 0.088 mmol) was dissolved in a solution of acetic anhydride (1.0 mL) and pyridine (1.0 mL) containing DMAP (several crystals) and the solution stirred at 18° C. for 26 h. The solution was then diluted with ethyl acetate (15 mL) and washed with NaHCO3 (a saturated solution in H2O, 20 mL) and citric acid (10% in H2O, 20 mL) dried over (MgSO4) and concentrated under reduced pressure. The residue was subjected to flash chromatograophy on silica gel (sequential elution with 2:1, 1:1 hexane/ethyl acetate) the relevant fractions (Rf 0.42 1:1 hexane/ethyl acetate) were concentrated giving the title compound (47 mg, 83%) as a white solid mp 251-2° C. IR (KBr disc, cm−1) 2937, 2840, 1769, 1718, 1603, 1545, 1507, 1475, 1456, 1414, 1295, 1266, 1201, 1141, 1117, 1036. 1H NMR (300 MHz, CDCl3) δ 7.31 (dd, J=2.1, 8.4 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.07 (s, 1H), 4.90 (m, 1H), 4.60 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.86 (s, 3H), 3.45 (s, 3H), 3.39 (s, 3H), 3.13 (m, 2H), 2.30 (s, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ 168.7 (C), 168.4 (C), 155.0 (C), 151.9 (C), 147.5 (C), 144.8 (C), 142.2 (C), 140.6 (C), 138.7 (C), 135.6 (C), 129.5 (CH), 127.6 (C), 127.2 (C), 125.4 (CH), 122.6 (C), 119.8 (C), 116.1 (C), 114.8 (C), 114.4 (C), 112.9 (CH), 111.7 (CH), 105.4 (CH), 105.0 (CH), 60.9 (CH3), 60.8 (CH3), 56.2 (CH3), 55.5 (CH3), 55.2 (CH3), 42.1 (CH2), 21.7 (CH2), 20.4 (CH3). MS (70 eV) m/z (%): 629 (53, M+·), 587 (100, M+·-CH2CO); HRMS calcd for C34H31NO11 629.1897. Found 629.1907.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O-:16])=[O:15])[C@H:11]([CH2:17][C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(O[CH2:28][CH:29]=[CH2:30])=O.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[CH2:30]([O:15][C:14]([N:12]1[CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:10][C@H:11]1[CH2:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1)=[O:16])[CH:29]=[CH2:28]
Reactant: Cn1ccnc1C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)[O-]
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1nccn1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2R,4R)-4-(t-butyldimethylsilyloxy)-2-{(1-methylimidazol-2-yl)methyl}pyrrolidineformate (20.0 g) in tetrahydrofuran (300 ml) and water (200 ml) was added dropwise a solution of allyl chloroformate (7.45 ml) in THF (20 ml), adjusting pH to 9.0~9.5 with 5N-aqueous sodium hydroxide solution, at -3°~1° C. over 10 minutes. The mixture was stirred at the same temperature for 50 minutes. To the reaction mixture was added ethyl acetate (600 ml) and ice water (400 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-{(1-methylimidazol-2-yl) methyl}pyrrolidine (20.5 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][NH:17][CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([N:17]1[CH2:16][CH2:15][C:14]2[NH:13][CH:12]=[C:11]3[C:20](=[O:21])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[C:10]3[C:19]=2[CH2:18]1)(=[O:24])[CH3:23]
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CNCC3
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
2-p-Chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one is treated with an excess of acetic anhydride with heating to obtain 8-acetyl-2-p-chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one, mp above 350°; IR: 1640,1670cm-1.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].O>CN(C)C=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13]
Reactant: O=C1CCc2ccccc2N1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1CCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A suspension of NaH in mineral oil (55-60%) (712 mg) was added to a solution of 3,4-dihydro-1H-quinolin-2-one (2.0 g, 13.6 mmol) in N,N-dimethylformamide (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. then 1-bromo-3-chloropropane (1.34 mL, 13.6 mmol) was added. The slurry was stirred for additional 16 h. at ambient temperature then water (50 mL) was added and the product was extracted with diethyl ether (2×50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by flash-chromatography (eluent: dichloromethane) to give 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol). KI (2.5 g, 15 mmol), K2CO3 (2.1 g, 15 mmol) and 4-butylpiperidine (1.8 mL, 15 mmol) were added to a solution of 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 60° C. for 16 h. The acetonitrile was evaporated in vacuo, water (50 mL) was added and the product was extracted with ethyl acetate (2×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash-chromatography (eluent: ethyl acetate) gave the title product. Yield: 2.06 g, 58%. Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+1+=329.5 (UV/MS(%)=100/100). 1H NMR (400 MHz, CD3OD): δ=0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broad d), 1.83 (2H, quin.), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t), 2.84-2.96 (4H, m), 3.99 (2H, t), 7.02 (1H, broad t), 7.16 (1H, broad d), 7.20 (1H, broad d), 7.25 (1H, broad t). 13C NMR (CD3OD): δ 13.2, 22.8, 24.3, 25.0, 28.9, 31.6, 31.9 (2C), 35.6, 36.2, 40.1, 53.8 (2C), 55.9, 115.2, 123.2, 127.0, 127.4, 127.9, 139.1, 171.5
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][N:5]2[CH2:4][CH2:3][S:2][CH2:7][CH2:6]2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CN1CCSCC1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CN1CCSCC1
Yield: 37.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-thiomorpholinoacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 83, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-thiomorpholinoacetyl)pyrrolidine-2-carboxamide (13.9 mg, 37.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.54 (d, 2H), 7.27 (m, 2H), 7.21-7.16 (m, 7H), 6.93 (m, 2H), 4.44 (m, 1H), 3.71 (m, 1H), 3.28 (m, 1H), 3.13 (m, 2H), 2.87 (m, 4H), 2.63 (m, 3H), 2.55 (m, 4H), 1.85 (m, 2H). MS (EI) for C30H32FN3O3S. found 534.7 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=O)[CH2:7]1)=[O:5])[CH3:2].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH2:34][NH2:35].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C.O>[CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([C@@H:9]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:10]2[NH:35][CH2:34][C:33]2[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=2[O:31][CH3:30])[CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(OC)c(CN)c1
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1[C@H](NCc1cc(OC)ccc1OC)[C@@H]2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A mixture of 23 (3.9 g, 10 mmol), 2,5-dimethoxybenzyl amine (1.9 g, 11 mmol) (Acta. Chem. Scand., 25. p. 2629 (1971)) and camphor sulfonic acid (120 mg) in toluene (40 ml) was heated at reflux with removal of water for 8 hours and then the solvent was removed. The residue was dissolved in small amount of THF (c.a. 5 ml) and this solution was added to a solution of sodium triacetoxyborohydride (5.3 g, 25 mmol) in acetic acid (100 ml) at room temperature. The mixture was stirred at room temperature for 4 hours and the solvent was removed. Water (25 ml) was added and the mixture was neutralized with NaHCO3 and extracted with EtOAc three times. The clude was purified by recrystallization from EtOAc to give 24 (2.4 g, 4.4 mmol, 44%).