Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([CH2:2][CH2:3][NH:4][C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][C:7]([O:9][CH3:10])=[O:8])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C=C(CC(=O)OC)NCCO
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C=C(CC(=O)OC)NCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
The solution of dimethyl 3-(2-hydroxyethylamino)-2-pentenedioate was cooled to 0° C., and triethylamine (235 mL, 170.6 g, 1.69 mol) was added in one portion. Methanesulfonyl chloride (168.8 g, 1.47 mol) was added dropwise via an addition funnel over 3.75 hours, with the temperature rising to 5°-7° C. The medium-yellow slurry darkened to yellow-orange as the last 10 mL methanesulfonyl chloride was added. The mixture was stirred at 0° C. for an additional 2 hours, and water (250 mL) added. The organic phase was washed with water (4×500 mL) and brine (250 mL), and dried overnight over anhydrous magnesium sulfate. After filtration, the solvents were evaporated on a rotary evaporator under reduced pressure at 50° C. to afford 310.0 g (93% yield) of dimethyl 3-(2-methanesulfonylethylamino)-2-pentenedioate as a red oil. The mesylenamine may be purified at this point, if necessary or desired, and may be converted to the haloenamine by the following method or used directly in Step 2, Alternate II.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O.ClCCl>[C:24]([NH:6][C@@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:4]([O:3][CH3:2])=[O:15])(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reaction time: 3.5 h
Yield: 92.4 %

Procedure:
200 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol), and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and hexanoyl chloride (13.8 ml, 0.1 mol) was slowly added, following by stirring for 3-4 hours. 200 ml of water was added to the reacted material, followed by extraction with 400 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by solidification with hexane and ethyl acetate, thereby obtaining a white solid (27.1 g, 92.5% yield) [hereinafter, referred to as Compound 1a].
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH2:30][CH2:31][CH3:32])=[N:23][C:24]=2Cl)(=O)C.[CH2:33]([NH2:35])[CH3:34]>O1CCOCC1.O>[CH2:33]([NH:35][C:24]1[C:25]2[N:26]=[CH:27][N:19]([C:20]=2[N:21]=[C:22]([S:29][CH2:30][CH2:31][CH3:32])[N:23]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4])[CH3:34]
Reactant: CCN
Reactant: CCCSc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Solvent: C1COCCO1
Solvent: O
Product: CCCSc1nc(NCC)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-(propylthio)purine (1.3 g) and ethylamine (1.6 ml) in dioxane (30 ml) and water (30 ml) were heated in a sealed autoclave at 110° for 20 hours. On cooling to room temperature, evaporation gave a residue which was recrystallised from ethyl acetate. Further purification by chromatography (SiO2, methanol:ethyl acetate, 1:15 as eluant) gave the sub-title compound (0.46 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]=[C:39]=[S:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:39]([NH:38][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)=[S:40])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 96%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[NH:13][N:14]=[CH:15][C:7]=12.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:12][C:10]1[N:9]=[C:8]2[N:13]([C:24]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[N:14]=[CH:15][C:7]2=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2cnn(C(=O)NCc3ccccc3)c2n1
Yield: 23.9 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (210 mg, 1 mmol) in DMF (2 mL) was treated with benzyl isocyanate (123 μL, 1 mmol) and a catalytic amount of DMAP, stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by preparative HPLC (MeOH/H2O gradient) to give the title compound (80 mg, 24%) as a pale yellow solid. Method Q 4-(2-Furyl)-1-(4-indolymethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (Example 65)
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3].[C:7]1(O)[CH:12]=[CH:11]C=[CH:9][CH:8]=1>>[C:1](=[O:6])([O:4][C:5]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1)[O:2][CH3:3]
Reactant: COC(=O)OC
Reactant: Oc1ccccc1
Product: COC(=O)Oc1ccccc1

Procedure:
A transesterification reaction was performed between dimethyl carbonate and phenol to obtain methyl phenyl carbonate. The obtained methyl phenyl carbonate was subjected to a disproportionation reaction to obtain a diphenyl carbonate product containing about 90 ppm by weight of methyl phenyl carbonate.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[Cl:25])[CH2:18][N:19]=[N+:20]=[N-:21])=[O:14])=[CH:11][CH:10]=1>C(O)C>[NH2:3][C:2]1[N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:15]([C:13](=[O:14])[C:12]3[CH:26]=[CH:27][C:9]([Cl:8])=[CH:10][CH:11]=3)[CH:16]=2)[N:20]=[N:21][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(C(=O)c2ccc(Cl)cc2)c1
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(Cl)c(C(=O)c3ccc(Cl)cc3)c2)c1N
Temperature: 0 °C
Yield: 60.3 %

Procedure:
To a stirred solution of sodium (0.147 g, 6.41 mmol) in ethanol (20 ml) under nitrogen atmosphere was added 2-cyanoacetamide (539 mg, 6.41 mmol) and the mixture was refluxed 10 minutes. The mixture was cooled slightly, 3-(4-chlorobenzoyl)-4-chlorobenzyl azide (1.51 g, 4.93 mmol) was added, and the mixture was refluxed 1 hour. The mixture was cooled to 0° C. and filtered. The product was washed with ice cold ethanol (2×5 ml), water (3×5 ml), ice cold ethanol (2×5 ml), and diethyl ether (10 ml), and dried at 50° C. for 3 hours under vacuum to provide 1.16 g (60%) of 5-amino-1-(3-[4-chlorobenzoyl]-4-chlorobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 189°-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:13](OCC)(=[O:17])[C:14]([O-:16])=[O:15]>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13](=[O:17])[C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: CCOC(=O)C(=O)[O-]
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cccnc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
10 g. (0.063 mol) of 3-bromopyridine in 80 ml. of dry THF was added dropwise to a -70° C. solution of butyl lithium (1.6M, 40.6 ml, 0.065 mol) dissolved in 120 ml. of dried THF over a 20 minute period. The resulting brown solution was stirred at -70° C. for 30 minutes and then transferred by nylon tubing under positive nitrogen pressure into a stirred 0° C. solution of ethyl oxalate (36.8 g, 0.25 mol) in 60 ml of dry THF. The solution was stirred at 0° C. for 45 minutes, quenched by addition of 50 ml. glacial acetic acid, warmed to room temperature and poured into 500 ml of water, adjusted to pH 7.0 with 750 ml saturated sodium bicarbonate and extracted with 2×500 ml ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to a brown oil; 24.7 g. This oil was flash chromatographed on silica gel eluted with 1:2 ethyl acetate hexane. A viscous yellow oil was obtained; 1.56 g, m/e 179, spectral data consistent with structure of title product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Br)([Br:12])=O>ClCCl>[Br:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=S(Br)Br
Reactant: Cc1cc(CO)ccn1
Solvent: ClCCl
Product: Cc1cc(CBr)ccn1
Reaction time: 1 h

Procedure:
To a solution of (2-methylpyridin-4-yl)-methanol (0.510 g, 4.14 mmol) in 8 mL of dichloromethane was added thionyl bromide (1.03 g, 4.97 mmol) dropwise. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride. The organic solution was washed 2× with water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 4-(bromomethyl)-2-methylpyridine that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 188.0 (81Br) for [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C:11]([CH3:26])([C:13]1[NH:14][C:15](=[O:25])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:18]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH3:30]OS(OC)(=O)=O.O>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:27])[NH:10][C:11]([CH3:12])([C:13]1[N:14]([CH3:30])[C:15](=[O:25])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:18]=1)[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1nc(-c2ccncn2)cc(=O)[nH]1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(C(C)(C)NC(=O)OCc2ccccc2)nc(-c2ccncn2)cc1=O
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 11 %

Procedure:
To a suspension of 0.13 g (0.36 mmol) of [1-Methyl-1-(6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-carbamic acid benzyl ester in 1.5 mL of anhydrous dioxane was added 0.003 g (0.39 mmol) of lithium hydride. The resulting mixture was allowed to stir at 40° C. for 45 minutes. After cooling down to room temperature, 0.058 g (0.46 mmol) of dimethylsulfate was added and reaction mixture was heated at 60° C. for 12 h. After cooling to 0° C., water was added and the mixture extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated. The residue was purified on preparative thin layer chromatography eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 95/5/0.5 to afford 0.015 g (11%) of the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:19])[CH3:18])[N:10]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:18])[CH3:19])[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:26])=[C:23]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)[CH:22]=1
Reactant: O=C(O)c1ccc(F)cc1-n1nccn1
Reactant: COc1cc(N2CC3CNCC3C2)nc(N(C)C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC3CN(C(=O)c4ccc(F)cc4-n4nccn4)CC3C2)nc(N(C)C)n1
Yield: 50 %

Procedure:
A mixture of [4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine (60.0 mg, 0.23 mmol), 4-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (52.0 mg, 50.5%). MS (ESI) mass calcd. for C22H25FN8O2, 452.49; m/z found [M+H]+. 1H NMR (CDCl3): 7.83-7.66 (m, 3H), 7.42-7.36 (m, 1H), 7.16-7.08 (m, 1H), 5.00-4.89 (m, 1H), 3.90-3.78 (m, 4H), 3.77-3.19 (m, 6H), 3.17-2.82 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cc(Cl)cc(Cl)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
Trans-methyl 2-(3,5-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.6 g, 1.49 mmol) (from example 55, step 1) was dissolved in MeOH (6.11 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.393 mL, 1.49 mmol) in water (0.611 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.091 mL, 1.49 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (7.71 mL, 46.24 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM and water were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated to yield crude trans-methyl 2-(3,5-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (300 mg, 54%). MS m/z 371 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=[C:4]([CH3:16])[N:3]=1.[OH-].[K+].[ClH:19]>C(O)C>[ClH:19].[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:12]([F:14])([F:13])[F:15])[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: COC(=O)c1c(C(F)(F)F)cc(C)nc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)c(C(=O)O)c(C)n1
Temperature: 25 °C
Yield: 99 %

Procedure:
Methyl 2,6-dimethyl-4-trifluoromethylpyridine-3-carboxylate (23.30 g, 99.9 mmol) was dissolved in ethanol (50 mL), followed by the addition of 5 mol/L aqueous solution of potassium hydroxide (50 mL, 250 mmol). The mixture was subjected to heating under reflux for 2 days. The reaction mixture was allowed to cool down to room temperature, and concentrated hydrochloric acid (15 mL) was added and concentrated under reduced pressure. The residue was azeotropically distilled three times with ethanol and toluene. The residue was suspended in ethanol under heat, and subsequent to filtration, the filtrate was concentrated under reduced pressure. The residue was azeotropically distilled twice with toluene, and subsequent to the addition of ether, the reaction product was collected by filtration to obtain the title compound (25.24 g, 99%) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55](=[O:62])[C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)[CH2:51][CH2:52]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccncc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and isonicotinoyl chloride hydrochloride as the starting materials in 30% yield. LCMS for C30H31ClN7O2 (M+H)+: m/z=556.1.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55](=[O:73])[C@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)([CH3:53])([CH3:52])[CH3:51]>C(#N)C>[C:50]([O:54][C:55](=[O:73])[C@H:56]([NH:72][C:12](=[O:14])[C@@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of the product from Example Z ((S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.8 g, 3.1 mmol) and triethylamine (1.6 mL, 6.2 mmol) HBTU (1.3 g, 3.4 mmol) in acetonitrile (15 mL) was treated with HBTU (1.54 g, 4.06 mmol). The resulting solution was treated with the product from Example B ((R)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (1.08 g, 3.30 mmol), and the resulting solution was stirred at room temperature for 30 minutes and allowed to stand overnight. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (100 mL) and washed sequentially with 0.6 M aqueous NaHCO3 solution, saturated aqueous NaCl solution, and water. The organic phase was dried over MgSO4 and activate charcoal, filtered, and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate/hexane) to give the title compound as a white solid (1.4 g, 79%), mp=38-40° C.
Reaction SMILES: [CH3:1][C:2]([CH3:51])([CH3:50])[C:3](=[O:49])[CH2:4][O:5][C:6]([C:8]1([C:39]([O:41]CC2C=CC=CC=2)=[O:40])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[C:28]([F:38])[CH:27]=4)[O:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7].C(OCC)(=O)C.O1CCCC1>[Pd].C([O-])([O-])=O.[Ca+2].C(O)C>[CH3:1][C:2]([CH3:51])([CH3:50])[C:3](=[O:49])[CH2:4][O:5][C:6]([C:8]1([C:39]([OH:41])=[O:40])[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[C:28]([F:38])[CH:27]=4)[O:23][N:22]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C

Procedure:
2 g of 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester 3,3-dimethyl-2-oxobutyl ester are added into round bottomed flask containing a solvent mixture of ethyl acetate/tetrahydrofuran [1/0.5] and stirred at room temperature to get a clear solution. Then 40 mL of ethanol are added followed by 0.6 g Pd/CaCO3. The mixture is stirred under hydrogen gas. After 30 mins 0.2 g of Pd/CaCO3 are added to the above reaction mixture and stirring under hydrogen is continued. Once the reaction gets completed 4 g of silica gel are added and the mixture stirred at RT for 10 mins, cooled to 0-5° C. and stirred for 20-30 mins. The slurry is filtered and washed with 40 mL ethyl acetate. The product along with Pd/CaCO3 on the funnel was leached with 200 mL, then 250 mL of a dichloromethane/methanol [2:1] mixture at RT and filtered. The product containing filtrate is concentrated and dried under vacuum at 35-40° C. to yield 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid (3,3-dimethyl-2-oxobutyl)ester (62).
Reaction SMILES: C(O)(=O)C(C)(C)C.[C:8]1([C:14]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:26]3[CH:25]=[C:24]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[C:34]1([C:14]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:26]3=[CH:25][C:24]4[NH:27][C:28]5[C:29]([C:23]=4[CH:22]=[C:21]3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc(Nc2ccc3c(c2)C(c2ccccc2)(c2ccccc2)c2ccccc2-3)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: ClCCl
Product: c1ccc(C2(c3ccccc3)c3ccccc3-c3cc4c(cc32)[nH]c2ccccc24)cc1
Temperature: 120 °C
Reaction time: 9 h

Procedure:
50 ml of pivalic acid are added to 15 g of (9,9-diphenyl-9H-fluoren-2-yl)phenylamine (36.6 mmol), 0.9 g of palladium(II)acetate (3.66 mmol) and 0.5 g of potassium carbonate (3.66 mmol), and the mixture is stirred at 120° C. for 9 h. After this time, 0.9 g of palladium(II)acetate (3.66 mmol) is added, and the mixture is stirred at 120° C. for a further 9 h. 200 ml of dichloromethane and 0.1 M Na2CO3 solution are then added. The mixture is partitioned between water and dichloromethane, the aqueous phase is extracted three times with dichloromethane, and the combined organic phases are dried over Na2SO4 and evaporated in a rotary evaporator. The residue is recrystallised from toluene/heptane. The yield is 6 g (14.6 mmol, 40%).