Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:27]#[N:28])=[N:21][CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH3:26][O:25][C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:27]=2[NH2:28]
Reactant: COc1cnc(C#N)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cnc2c(N)nc3ccccc3c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloro-5-methoxypicolinonitrile (from step 1) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 50-100% ethyl acetate in hexane to give 2-methoxybenzo[f][1,7]naphthyridin-5-amine.
Reaction SMILES: [C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=4[C:12]3=[C:11](Br)[C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=4[C:12]3=[C:11]([C:16]3[CH:15]=[CH:14][N:13]=[CH:12][CH:21]=3)[C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3ccncc3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Yield: 100.4 %

Procedure:
A solution of 50 mg of 18d, 60 mg of K2CO3, 30 mg of 4-pyridylboronic acid-pinacolester and 15 mg of Pd(PPh3)4 in 2.5 ml of degassed 90% aq. dimethoxyethane was heated at 95° C. under N2 for 16 hr. The mixture was cooled and poured onto 1N NaOH and the product was extracted with ethyl acetate. The organic layer was washed twice with water, dried, concentrated and the residue was chromatographed on silica gel (using a gradient of heptane/acetone as eluent). The product was treated with ether, to give 25 mg of 18f as white crystals. Mp: 218-219° C. MS-ESI: [M+1] 490.17.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(#N)C>[O:12]=[C:8]1[C:7]2=[C:2]([NH:1][C:21](=[O:23])[CH3:22])[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(c(N)n1)C(=O)OCC2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)cc2c1C(=O)OCC2
Yield: 88.6 %

Procedure:
8-amino-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (200 g, 1.122 mmol) was dissolved in 6 mL of anhydrous acetonitrile, and then dropwisely added with triethylamine (0.63 mL, 4.490 mmol) and actic anhydride (0.42 mL, 4.490 mmol) in this order and then heated to reflux for about 20 hours under the nitrogen atmosphere. The mixture was concentrated under reduced pressure, added with 15 mL of a saturated solution of sodium carbonate and 15 mL of distilled water and then extracted twice with 40 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, and filtered. A silica gel column chromatography (5% MeOH/MC) was performed on the resulting residue and 219 mg (89%) of N-(1-oxo-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-8-yl)-acetamide was obtained in white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:13]([CH:16]=[C:17](SC)[S:18][CH3:19])([O-:15])=[O:14]>>[N+:13]([CH:16]=[C:17]([S:18][CH3:19])[NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:15])=[O:14]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ncccc1O
Product: CSC(=C[N+](=O)[O-])NCCSCc1ncccc1O

Procedure:
By the procedure of Example 4(i), 3-hydroxy-2-[(2-aminoethyl)- thiomethyl]pyridine (from the dihydrobromide (4.2 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) to give 1-nitro-2-methylthio-2-[2-((3-hydroxy-2-pyridyl)methylthio)-ethylamino]ethylene which, on reaction with methylamine by the process of Example 3(ii) gives 1-nitro-2-methylamino-2-[2-((3-hydroxy-2-pyridyl)methylthio)ethylamino]ethylene.
Reaction SMILES: Cl.C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3[CH:14]=[CH:15][N:16]=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)N(CC2)C1>C(OC(C)C)(=O)C>[NH:16]1[C:17]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15]1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: c1ccc2[nH]ccc2c1
Temperature: 2.5 °C
Reaction time: 0.21 h
Yield: 157.7 %

Procedure:
In a 5-L cylindrical reactor, 3 N HCl (750 mL) was added to the eutomer cinchonidine salt (256 g, 0.485 mol) in isopropyl acetate (1.5 L) at 20-25° C. The mixture was stirred for 10-15 min then separated into two layers. The isopropyl acetate layer was set aside. The lower aqueous layer was extracted with isopropyl acetate (250 mL). The combined isopropyl acetate layers were with H2O (750 mL). Heptane (1.75 L) was added to the isopropyl acetate layer then the isopropyl acetate and heptane solution (3.7 L) was distilled under atmospheric pressure to ˜¼ its original volume, approximate 1.0 L. Heptane (1 L) was added over 15-20 min at 85-90° C. then the mixture cooled to 0-5° C. over 1-2 h. The mixture was stirred at 0-5° C. for 1-2 h then filtered through a Buchner funnel lined with polypropylene cloth. The solid was washed with heptane (2×150 mL) then the product dried under vacuum under a bed of N2 for 14 h to give 89.6 g (29.9% overall yield from racemic acid) of the eutomer indole acid as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[F:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH:16]=[N:15][CH:14]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(-c2cncc(F)c2)cncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 73.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (790 mg, 3.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (LXX) (1.01 g, 4.35 mmol), K3PO4 (1.15 g, 5.44 mmol), water (10 mL) and DMF (10 mL) was degassed with argon thrice. Pd(PPh3)4 (209 mg, 0.18 mmol) was added to the reaction and the solution was heated at 90° C. for 4 h. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→1.5:98.5 MeOH[7N NH3]:CHCl3) to give 5′-fluoro-5-nitro-3,3′-bipyridin-4-amine (LXXI) as a yellow solid (626 mg, 2.67 mmol, 74% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.62 (brs, 2H), 7.86-7.89 (m, 1H), 8.15 (s, 1H), 8.47-8.48 (m, 1H), 8.67 (d, J=2.7 Hz, 1H), 9.07 (s, 1H); ESIMS found C10H7FN4O2 m/z 235 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.C(O[CH:9]=[CH:10][C:11]([N:13]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])C.[OH-].[Na+]>>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([N:13]2[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:9]=[CH:10][C:11]2=[O:12])[CH2:21][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC=CC(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccc2ccccc2n1C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
To a concentrated sulfuric acid (15 ml) is added in portions N-(β-ethoxyacryloyl)-N-(1-benzyl-4-piperidinyl)aniline (1.1 g) at 60° C. After stirring the mixture at the same temperature for 15 minutes, the reaction mixture is poured into ice-water, made alkaline with a 10% aqueous sodium hydroxide solution and extracted with dichloromethane. After the extract is concentrated by distilling off the solvent, the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) and recrystallized from ethyl acetate to give 1-(1-benzyl-4-piperidinyl)carbostyril (0.8 g) as white powders, m.p. 97°-99° C.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][NH2:17])[N:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:19][C:20]1[C:21]([CH:27]=O)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:19][C:20]1[C:21]([CH2:27][NH:17][CH2:16][CH2:15][C:13]2[N:12]=[CH:11][N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=3)(=[O:9])=[O:8])[CH:14]=2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCN)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(CCNCc3ncc(C)cc3C)c2)cc1

Procedure:
Using General Procedure B: Reaction of 2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethylamine and 3,5-dimethyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8](CC2C=C3C(=CC=2)C[C@@H](CN)CC3)[CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=C3C(=CC=2)C[C@@H](N)CC3)CC2CCOCC2)=CC=1.OC1C=CC(C(O)=O)=NC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CN(Cc2ccc3c(c2)CC[C@H](CN)C3)CC2CCOCC2)cc1
Agent: COc1ccc(CN(Cc2ccc3c(c2)CC[C@H](N)C3)CC2CCOCC2)cc1
Agent: O=C(O)c1ccc(O)cn1
Product: COc1ccc(CNCC2CCOCC2)cc1

Procedure:
In Table 2, compounds which were prepared by reacting the appropriate acids with ((S)-6-{[(4-methoxybenzyl)(tetrahydropyran-4-ylmethyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl)methylamine or, correspondingly, (S)-6-{[(4-methoxybenzyl)(tetrahydropyran-4-ylmethyl)-amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-ylamine according to method G and subsequent detachment of the 4-methoxybenzyl group according to method F are compiled. To prepare examples 2-06, 2-07 and 2-08, ((S)-6-{[(4-methoxybenzyl)(tetrahydropyran-4-ylmethyl)-amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl)methylamine was reacted according to method G with 5-hydroxypyridine-2-carboxylic acid, the resulting amide was alkylated according to method D with the appropriate alkyl bromides on the phenolic hydroxyl group, and, finally, the 4-methoxybenzyl group was removed according to method F.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:3][CH:2]=1.[ClH:15]>CO.[OH-].[OH-].[Pd+2]>[ClH:15].[NH:1]1[CH2:2][CH2:3][CH:4]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:5][CH2:6]1
Reactant: CCOP(=O)(OCC)c1ccncc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCOP(=O)(OCC)C1CCNCC1
Reaction time: 168 h

Procedure:
Diethyl pyridin-4-ylphosphonate (3.8 g, 17.66 mmol) and palladium hydroxide on carbon (1.240 g, 1.766 mmol) were taken up in MeOH (90 mL)/HCl (10 mL, 20.00 mmol). The suspension was agitated under H2 @ 40-50 psi for 7 days. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give diethyl piperidin-4-ylphosphonate hydrochloride as a green gum. 1H NMR (DMSO-d6, 600 MHz) δ 9.26 (br s, 1H), 8.84 (br s, 1H), 3.96 (m, 4H), 3.20 (m, 2H), 2.80 (m, 2H), 2.10 (m, 1H), 1.84 (m, 2H), 1.68 (m, 2H), 1.19 (t, J=7.2 Hz, 6H). MS: cal'd 222 (MH+), exp 222 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][CH3:14])[C:3]=1[C:15]([NH2:17])=[O:16].N[C:19](N)=[O:20].CC(O)=O>[OH-].[Na+]>[CH2:13]([C:4]1[C:3]2[C:15](=[O:16])[NH:17][C:19](=[O:20])[NH:1][C:2]=2[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)[CH3:14]
Reactant: CCc1nn(-c2ccccc2)c(N)c1C(N)=O
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nn(-c2ccccc2)c2[nH]c(=O)[nH]c(=O)c12
Temperature: 200 °C
Reaction time: 1 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed 5-amino-3-ethyl-1-phenyl-1H-pyrazole-4-carboxamide (1 g, 4.35 mmol, 1.00 equiv) at room temperature. To the resulting mixture was then added urea (1.75 g, 29.17 mmol, 6.70 equiv), in portions at room temperature. The resulting solution was stirred for 1 h at 200° C. The resulting mixture was then cooled to room temperature. The residue was dissolved in sodium hydroxide (250 mL). The pH value of the solution was adjusted to about 5 with AcOH (conc.). The solids were collected by filtration to yield 3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione as a white solid. MS (m/z): 257 [MH+].
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH:29]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:22][N:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[NH4+:53].C(=O)([O-])O.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C.C(OCC)(=O)C.O1CCCC1>[CH3:46][S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH:29]([C:28]2[NH:53][C:25]([C:23]3[S:24][C:20]([CH2:19][OH:18])=[N:21][N:22]=3)=[CH:26][CH:27]=2)[CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:38][CH:39]=1)(=[O:45])=[O:44]
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](OCc1nnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CO)s3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a solution of 1-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3,4-thiadiazol-2-yl]-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.95 g) in acetic acid (20 mL) was added ammonium acetate (3.41 g), and the mixture was stirred at 110° C. for 30 min. The reaction mixture was cooled to room temperature, and neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give a crude product (1.9 g). To a solution of the obtained crude product in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution) (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 min and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.0 g, yield 81%) was obtained as white crystals from a fraction eluted with ethyl acetate. melting point 199-201° C. MS: 448 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][C@H:21](OS(C)(=O)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N:29]1([CH:21]2[CH2:22][CH2:23][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([N:3]4[CH2:4][CH2:5][C:6]5([CH2:7][CH2:8][O:9][CH2:10][CH2:11]5)[C:2]4=[O:1])=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N(c2ccc(C3CCC(N4CCCC4)CC3)cc2)CCC12CCOCC2
Temperature: 80 °C

Procedure:
Cis-Methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and pyrrolidine (20 mg, 0.28 mmol, 4 equiv.) were dissolved in anhydrous CH3CN (2 mL). To this colorless solution was added powder K2CO3 at r.t. The suspension was heated in an oil bath maintained at 80° C. for 24 h. The suspension was concentrated to dryness. The residue was taken in water (2 mL) and DCM (2 mL). The two layers were separated, and the aqueous layer was extracted with DCM (2 mL×2). The combined DCM extracts were washed with sodium bicarbonate (2 mL), brine (2 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5% of MeOH in DCM and 5% 7N NH3 of MeOH solution in DCM to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Mg]Cl)(C)C.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]C(Cl)=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=1)[CH3:2]
Reactant: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of malonic acid monoethyl ester (16.9 g, 128 mmol) in dry THF (200 mL) was cooled to -78° C. under nitrogen, treated dropwise with 130 mL of isopropyl magnesium chloride (2.0 M in THF; 260 mmol), and stirred at -78° C. for 45 minutes. A solution of 3-(4-nitrophenyl)propanoyl chloride prepared in Example EE (13.5 g, 64 mmol) in dry THF (100 mL) was added dropwise. When addition was complete, the reaction mixture was stirred at -78° C. for 1 hour and then allowed to warm to room temperature, where the solution was stirred for 3 more hours. A mixture of ice (50 mL) and 3N HCl (100 mL) was added. The solution was extracted with EtOAc, and the combined extracts were washed with brine and dried (MgSO4). Concentration gave the title compound. 1H NMR (CDCl3) δ 1.21 (t, 3 H), 2.88-3.00 (m, 4 H), 3.40 (s, 2 H), 4.13 (q, 2 H), 7.32 (d, 2 H), 8.09 (d, 2 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:69])[CH2:3][CH:4]1[CH2:18][N:17](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15][N:14](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]1S(C1C=CC(C)=CC=1)(=O)=O.OS(O)(=O)=O.C(O)C.C(OCC)C>CC#N>[CH3:1][CH:2]([CH3:69])[CH2:3][CH:4]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC(CC(C)C)N(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC#N
Solvent: CCO
Product: CC(C)CC1CNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 69 h
Yield: 20 %

Procedure:
A mixture of 2-(2-methylpropyl)-1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 5C (14.1 g, 0.0135 mole) and concentrated H2SO4 (50 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 69 h. To the resulting brown solution ethanol (70 mL) was added dropwise with stirring at 0° C., followed by ethyl ether (1l). The brown solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution washed with ethyl ether. A small amount of solid was removed by filtration, the pH was adjusted to 10-11 with 10N NaOH and the solvent was removed in vacuo. Ethanol (2×250 ml) was then added and removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and filtered at room temperature. The filtrates were combined, the solvent was removed in vacuo and the residue was dissolved in THF and filtered. The solvent was removed in vacuo to give the crude product as a tan oil which was then dissolved in CH3CN and filtered to remove insoluble impurities. Crystallization occurred upon cooling the filtrate to -20° C. Recrystallization from cold (-20° C.) CH3CN gave 715 mg (20% yield) of the product as a white crystalline solid: mp 70°-6° C.; 1H NMR (CDCl3) δ0.89 (d,J=6.5 Hz, 3 H), 0.90 (d, J=6.6 Hz, 3 H), 1.13 (m, 1 H), 1.39 (m, 1 H), 1.64 (sept, J=6.3 Hz, 1 H), 2.05 (br s, 5 H), 2.34 (m, 1 H), 2.75 (m, 18 H); Exact mass (M+Li)+ : calcd. 278.2896; found, 278.2919 (C14H33N5Li).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].[OH-].[K+].I[CH3:38]>CS(C)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH3:38])=[CH:23][CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (2S,4R)-1-[2-(3-acetyl-5-hydroxy-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 579 (28.0 mg, 0.057 mmol) in DMSO (2 mL) was treated with potassium hydroxide (15.0 mg, 0.257 mmol). The mixture was stirred at RT for 5 min, followed by addition of iodomethane (0.006 mL, 0.089 mmol) and stirring at RT for 60 h. The reaction mixture was partitioned between water and CH2Cl2 and the aqueous layer was extracted with CH2Cl2 (2×). The combined organics were washed with brine (3×), dried (phase separator) and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, flow: 20 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford after lyophilization of the purified fractions the title compound as a solid. MS (LC/MS): 504 [M+H]+, 526 [M+Na]+; tR (HPLC conditions k): 3.38 min.