Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([NH:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1C(=O)C2C(=CC=CC=2)C1=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9](=[O:10])[NH:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)NOCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NOCCCCN
Temperature: 80 °C
Reaction time: 65 h
Yield: 30.7 %

Procedure:
Hydrazine hydrate (1.0 ml, 20 mmol) was added to a solution of 2-(4-(tert-butoxycarbonylaminoxy)butyl)isoindole-1,3-dione (2.08 g, 6.22 mmol) in ethanol (8.0 ml). The reaction mixture was stirred at 80° C. for 65 h. The solvent was removed in vacuo. The residue was dissolved in toluene (10 ml) and the solvent was removed in vacuo. The residue was suspended in 1 N hydrochloric acid (10 ml). The precipitation was removed by filtration and was washed with water (2 ml). The filtrate and the wash-liquids were combined and made basic with potassium carbonate. The solution was extracted with dichloromethane (4×20 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 0.39 g of N-(4-aminobutoxy)carbamic acid tert-butyl ester. Potassium carbonate (3 g) was added to the aqueous phase, which was extracted with dichloromethane (3×20 ml). These combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo to give another 0.39 g of N-(4-aminobutoxy)carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:13](=[C:16]([OH:21])[C@H:17]([OH:20])[CH:18]=O)([CH3:15])[CH3:14].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[CH:18][C@H:17]([C:16](=[C:13]([CH3:15])[CH3:14])[OH:21])[OH:20]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC(C)=C(O)[C@H](O)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(CN=C[C@@H](O)C(O)=C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 2,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4Å and, after 20 minutes, 0.7 g (5.4 mmol) of isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for 1 hour. The organic solution of isopropylidene-L-glyceraldehyde (2,4-dimethoxybenzyl)imine obtained is cooled to -20° C. under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. A solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is then added dropwise within 1 hour and the mixture is subsequently stirred at room temperature overnight. The mixture is washed three times with 100 ml of water each time and with 100 ml of sodium chloride solution and then dried over sodium sulphate. The organic solution is evaporated and the residue is chromatographed on silica gel (230-400 mesh) while eluting with hexane/ethyl acetate (1:1). There are obtained 1.77 g (70%) of N-[(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [α]D =+41° (c=0.8 in chloroform); MS: 466 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[OH:5].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.C([O-])(O)=O.[Na+].O>O1CCOCC1>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([NH:2][CH2:3][C@@H:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[OH:5])[CH:19]=1
Reactant: NC[C@H](O)c1ccc(F)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O[C@@H](CNc1cc(Cl)ncn1)c1ccc(F)cc1
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A suspension of (R)-2-amino-1-(4-fluoro-phenyl)-ethanol hydrochloride (500 mg, 2.61 mmol), 4,6-dichloropyrimidine (353 mg, 2.37 mmol), and NaHCO3 (1.39 g, 16.6 mmol) in dioxane (10 mL) was heated in a 100° C. bath for 19 h and cooled to rt. Water (10 mL) was added, and the mixture, containing solid, was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound as a white solid (415 mg, 59%) in 90% enantiomeric excess (Chiralcel AD-H column, supercritical CO2).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14].[CH2:25]([N:29]([CH2:39][CH2:40][CH2:41][CH3:42])[C:30]([C:32]1[C:36]([Cl:37])=[C:35]([CH3:38])[NH:34][N:33]=1)=[O:31])[CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:37][C:36]1[C:32]([C:30](=[O:31])[N:29]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:25][CH2:26][CH2:27][CH3:28])=[N:33][N:34]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[O:14])[C:35]=1[CH3:38]
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 125 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (645 mg, 1.97 mmol) and N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (1.07 g, 3.94 mmol) in NMP (9.9 mL) was added K2CO3 (1.09 g, 7.88 mmol). The resulting reaction mixture was stirred at 125° C. for 3 h, cooled to room temperature and quenched with 10% aq. LiCl solution. The solution was extracted with EtOAc (3×) and the combined organic extracts were washed with 10% LiCl (3×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (25% EtOAc/CHCl3) to afford the title compound (930 mg, 81%). 1H NMR (DMSO-d6, 2:1 mixture of amide rotamers) δ 8.32 (s, 0.5H), 8.23-8.13 (m, 1H), 8.11-8.00 (m, 1H), 7.76-7.87 (m, 0.5H), 7.28-7.08 (m, 3.5H), 7.03-6.94 (m, 0.5H), 4.87-4.51 (m, 2H), 4.43-4.27 (m, 2.5H), 3.86-3.75 (m, 0.5H), 3.63-3.32 (m, 3H), 3.23-3.07 (m, 1H), 3.05-2.94 (m, 1H), 2.85-2.62 (m, 2H), 2.27 (s, 2H), 2.22 (s, 1H), 1.48-1.09 (m, 9H), 1.04-0.92 (m, 2H), 0.90-0.82 (m, 3H), 0.70-0.63 (m, 3H); MS(ESI+) m/z 579.4 (M+H)+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[OH-].[Na+].[C:12]([OH:19])(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=[O:16].Cl>CCO>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:17][C:15](=[O:16])[CH2:14][CH2:13][C:12]([OH:19])=[O:18])=[CH:3][CH:2]=1
Reactant: CC(=O)CCC(=O)O
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=CC(=O)CCC(=O)O)cc1
Yield: 19.4 %

Procedure:
4-Tolualdehyde (39.6 g, 0.33 mol) and 2M NaOH solution (230 ml) are added to a solution of levulinic acid (39.5 g, 0.34 mol) in EtOH (85 ml) over 1 hour. The resulting clear solution is poured into ice and acidified with 6M HCl. The resulting gum obtained is crystallised with acetone/water and recrystallised from CH2Cl2 to yield 14.0 g of 6-(4 methylphenyl)-4-oxo-hex-5-enoic acid as colourless crystals m.p. 129-130.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:1][C@@H:2]1[N:7]([C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=C(O)Cc1ccccc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cc1ccccc1
Reaction time: 3 h
Yield: 83 %

Procedure:
3-Methyl-(3S)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (250 mg), benzeneacetic acid (210 mg) and Hunigs base (450 □l) were dissolved in DMF (10 ml) and HATU (720 mg) added portionwise over 2 min. The reaction mixture was stirred for 3 h, diluted with EtOAc, washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica with 25% EtOAc/isohexane as eluent to give the sub-title compound (330 mg)
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[C@H:2]([C:28]([OH:30])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].CN1CCOCC1.Cl.[NH2:56][C@H:57]([C:61]([NH:63][C@H:64]([C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)=[O:73])[CH2:65][C:66](=[O:71])[O:67][CH2:68][CH:69]=[CH2:70])=[O:62])[CH:58]([CH3:60])[CH3:59]>CN(C)C=O.O.C(OCC)(=O)C.C(#N)C>[NH:1]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[C@H:2]([C:28]([NH:56][C@H:57]([C:61]([NH:63][C@H:64]([C:72]([O:74][CH2:75][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1)=[O:73])[CH2:65][C:66](=[O:71])[O:67][CH2:68][CH:69]=[CH2:70])=[O:62])[CH:58]([CH3:59])[CH3:60])=[O:30])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:10])=[O:11]
Reactant: C=CCOC(=O)C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)OCc1ccccc1
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: C=CCOC(=O)C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CCC(C)(C)O2)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
In a 3 neck, 3 L flask equipped with a mechanical stirrer is placed 17.25 g (26 mmol) Fmoc-Arg(Pmc) and 300 mL acetonitrile and the mixture is stirred at ambient temperature until a clear solution is obtained. Benzotriazolyloxy-tris[pyrrolidino]-phosphonium hexafluoroacetate (PyBOP) is added, the solution cooled to 2° C., and 2.6 g (26 mmol) of N-methylmorpholine is added, forming a white tar. Dimethylformamide (52 mL) is added slowly until the tar dissolves, and the mixture is stirred at 3° C. for 30 minutes. A solution of HCl.Val-Asp(OAllyl)-OBzl) (10.4 g, 26 mmol) in 39 mL of dimethylformamide is added over 20 minutes at 2-3° C., followed by N-methylmorpholine (7.5 mL) to attain pH 7. Cooling is ceased, and the mixture is stirred for 2.5 hours. The mixture is then diluted with 250 mL water and 250 mL ethyl acetate. The ethyl acetate layer is removed and washed with water (2×100 mL) and brine (2×100 mL) and concentrated to afford a white solid which is crystallized from 175 mL ethyl acetate to give 18.5 g Fmoc-Arg(Pmc)-Val-Asp(OAllyl)-OBzl (95A %). The ethyl acetate filtrate is concentrated and the gummy residue triturated with ethyl acetate to afford an additional 3.12 g of product. (Mcalc 1007; M+1obsvd 1008).
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[N:4][N:5]2[C:10]=1[C:9]1[S:11][CH:12]=[CH:13][C:8]=1[N:7]=[CH:6]2.[C:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:16].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[CH3:14][C:3]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:15]#[N:16])=[CH:19][CH:20]=2)=[C:10]2[N:5]([CH:6]=[N:7][C:8]3[CH:13]=[CH:12][S:11][C:9]=32)[N:4]=1
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: Cc1nn2cnc3ccsc3c2c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn2cnc3ccsc3c2c1-c1ccc(CC#N)cc1
Temperature: 95 °C
Reaction time: 10 h
Yield: 64.2 %

Procedure:
A microwave vial charged with 9-bromo-8-methylpyrazolo[1,5-c]thieno[2,3-e]pyrimidine (48.0 mg, 0.179 mmol), [4-(cyanomethyl)phenyl]boronic acid (from Aldrich, 51.9 mg, 0.322 mmol), sodium carbonate (47.4 mg, 0.448 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (15 mg, 0.018 mmol), DMF (1.3 mL) and water (0.13 mL) was purged with N2 and then stirred at 95° C. for 10 h. The reaction was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (35 mg, 64%). LCMS calculated for C17H13N4S (M+H)+: m/z=305.1. Found: 305.0.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[NH2:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26](OC)(OC)[CH3:27]>O>[CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[O:22][CH:25]=[C:26]([CH3:27])[N:21]=2)=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(CBr)OC
Reactant: NC(=O)c1ccc(OCCNC(=O)OCc2ccccc2)cc1
Solvent: O
Product: Cc1coc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)n1
Temperature: 130 °C
Yield: 46.5 %

Procedure:
[2-(4-Carbamoyl-phenoxy)-ethyl]-carbamic acid benzyl ester (322 mg, 1.02 mmol) and 1-bromo-2,2-dimethoxypropane (3.8 g, 20.4 mmol) were combined in a round-bottomed flask and heated to about 130° C. for about thirty minutes. The reaction mixture was then cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate, the combined extracts dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography (1:1 hexanes/ethyl acetate) to afford the desired oxazole product (167 mg, 47% yield). LRMS ([M+H]+)=353.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10]CC)=[O:9])[NH:5][C:6]=1[CH3:7].ClC1C=C(C(O)=O)NC=1C>>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1[nH]c(C)c(Cl)c1C
Agent: Cc1[nH]c(C(=O)O)cc1Cl
Product: Cc1[nH]c(C(=O)O)c(C)c1Cl

Procedure:
Title compound was synthesized from ethyl 4-chloro-3,5-dimethyl-1H-pyrrole-2-carboxylate (Intermediate 76) by an analogous method to Intermediate 8.
Reaction SMILES: N#N.Br[C:4]1[C:5]([NH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([NH:16][O:17][CH3:18])=[O:15])=[CH:6][C:7]([Cl:10])=[N:8][CH:9]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.[Na+].[Br-].[F-].[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.C1(C)C=CC=CC=1>[Cl:10][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([NH:16][O:17][CH3:18])=[O:15])[C:4]([CH:23]2[CH2:25][CH2:24]2)=[CH:9][N:8]=1
Reactant: OB(O)C1CC1
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1C1CC1
Temperature: 100 °C
Yield: 52.3 %

Procedure:
In a sealable tube toluene (50 mL) was degassed with N2 at 50° C. for 15 min and to this 2-(5-bromo-2-chloro-pyridin-4-ylamino)-N-methoxy-benzamide (1.5 g, 4.21 mmole, 1 eq), cyclopropylboronic acid (1.4 g, 16.85 mmole, 4 eq) and Pd(PPh3)4 (0.24 g, 0.21 mmole, 0.05 eq) were added and resulting mixture was degassed for 30 min. To this NaBr (0.44 g, 4.33 mmole, 1.03 eq) and a solution of KF (0.8 g, 13.90 mmole, 3.3 eq) in H2O (3 mL) were added; again degassed with N2 for 15 min. The tube was sealed and the resulting mixture was heated at 100° C. for 24 h. After completion of reaction, reaction mixture was allowed to cool at room temperature, poured into water (100 mL) and extracted with toluene (2×50 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by washing with 0.5% DCM-Et2O to give titled compound as pale yellow solid (0.7 g, 53%). 1H-NMR (400 MHz, DMSO-d6): δ 0.57-072 (m, 2H), 0.97-1.10 (m, 2H), 1.62-1.75 (m, 1H), 3.68 (s, 3H), 7.02 (s, 1H), 7.11-7.20 (m, 1H), 7.51-7.67 (m, 3H), 7.94 (s, 1H), 9.62 (s, 1H), 11.92 (brs, 1H). LC-MS [M+H]+=318.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH:16]=C.[OH2:18]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH:16]=[O:18]
Reactant: O
Reactant: C=CCCCc1nnc(-c2ccccc2)n1C
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: Cn1c(CCCC=O)nnc1-c1ccccc1

Procedure:
To a solution of 4-methyl-3-(4-penten-1-yl)-5-phenyl-4H-1,2,4-triazole (196 mg, 0.86 mmol) in THF/H2O (7.5/1.5 ml) were added OsO4 (4% solution in water, 0.04 mmol) and NalO4 (2.6 mmol). The solution was stirred o.n. at r.t. Water was added and product was extract with DCM. The organic phase was separated, dried over Na2SO4 and filtered. Volatiles were evaporated in vacuo to give 178 mg of the title compound as an oil, which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15]Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:21]=1[CH2:22][OH:23].[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][O:23][CH2:22][C:21]2[CH:24]=[C:25]([Br:28])[CH:26]=[CH:27][C:20]=2[F:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OCc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCCC(CCBr)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCOCc2cc(Br)ccc2F)C1
Temperature: 25 °C

Procedure:
In a 25 ml round bottom flask, 2-[1-(t-butoxycarbonyl)piperidin-3-yl]ethyl bromide (1.011 g, 3.46 mmol) was dissolved in N,N-dimethylformamide (9 ml). Sodium iodide (1.037 g, 6.92 mmol) was added and the resulting mixture was stirred at ambient temperature for ten minutes. The 2-fluoro-5-bromobenzyl alcohol (0.852 g, 4.15 mmol) and sodium hydride (60%, 208 mg, 5.19 mmol) were then added and the resulting mixture began to froth and exotherm. After thirty minutes, the solution cooled and solidified. Three milliliters of N,N-dimethylformamide was added and the mass was slurried and stirred for three more hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between brine and diethyl ether. The organic fraction was washed six times with brine, and then dried over sodium sulfate. The desired title product was further purified by liquid chromatography.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]([F:33])([C:29]([F:32])([F:31])[F:30])[CH2:21][NH:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26]>>[CH3:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:25](=[O:26])[CH2:24][C:23]([NH:22][CH2:21][C:20]([F:33])([F:19])[C:29]([F:30])([F:32])[F:31])=[O:28])[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]1=2
Reactant: O=C(O)CC(=O)NCC(F)(F)C(F)(F)F
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CN1C(=O)[C@@H](NC(=O)CC(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-Methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: [CH:1]1([C:7](=O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[C:14]1([C@@H:20]2[CH2:22][C@H:21]2[NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]1([CH:7]([NH:23][C@@H:21]2[CH2:22][C@H:20]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(=O)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of 1-cyclohexylethanone (95 mg, 0.751 mmol) in 1,2-dichloroethane (DCE) (40 mL) and acetic acid (0.052 mL, 0.901 mmol) was added [(trans)-2-phenylcyclopropyl]amine (100 mg, 0.751 mmol). The reaction mixture was stirred for 2 hour at room temperature, then sodium triacetoxyborohydride (477 mg, 2.252 mmol) was added and the reaction mixture was stirred 3 hours at room temperature. The reaction mixture was quenched with saturated NH4Cl. Water (20 mL) followed by dichloromethane (40 mL) were added. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The solid was suspended in diethylether, sonicated and filtered. trans-N-(1-Cyclohexylethyl)-2-phenylcyclopropanamine (48 mg, 0.187 mmol, 24.95% yield) was isolated as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.11-9.35 (m, 1H), 8.80-9.03 (m, 1H), 7.27-7.42 (m, 2H), 7.13-7.27 (m, 3H), 3.23 (br. s., 1H), 2.91 (d, J=2.78 Hz, 1H), 2.57 (ddd, J=3.54, 6.44, 9.98 Hz, 1H), 1.68-1.87 (m, 4H), 1.57-1.68 (m, 2H), 1.46-1.57 (m, 1H), 1.26-1.42 (m, 1H), 1.18-1.24 (m, 3H), 0.95-1.18 (m, 4H); LC-MS Rt=0.83 min; MS (ESI): 244.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Cl[CH2:18][CH2:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21]>CN1C(=O)N(C)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:18][CH2:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21])[N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cc1nc(-c2cc(F)cc(F)c2)n[nH]1
Reactant: CC(C)(CCCl)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN1CCCN(C)C1=O
Product: Cc1nc(-c2cc(F)cc(F)c2)nn1CCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
3.74 g (19 mmol) 3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazole in 25 mL DMPU are reacted with 0.92 g (23 mmol, 60%) sodium hydride, 6.37 g (29 mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate and 1.27 g (3.5 mmol) tetrabutylammonium iodide analogously to intermediate product 1c). Oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[K+].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C([O-])=O.CCN(CC)CC.[Mg+2].[Cl-].[Cl-]>CC#N>[CH2:18]([O:17][C:11](=[O:16])[CH2:12][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1])=[O:8])[CH3:19]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1sccc1Cl

Procedure:
Prepared from 3-chloro-2-thiophenecarbonyl chloride[CAS-No. 86427-02-3] by reaction with ethyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a brown oil (6.84 g).