Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C([O-])(=O)C=C.[BH4-].[Na+]>[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Co](Cl)Cl>[NH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]([CH3:13])[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:3][CH:4]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Co]Cl
Agent: [Pd+2]
Agent: [Pd]
Product: CC(C(=O)OC(C)(C)C)c1ccc(CCN)cc1

Procedure:
p-Bromophenylacetonitrile is first condensed with t-butyl acrylate under conditions of the palladium acetate catalyzed Heck reaction. The resulting acrylate is hydrogenated with palladium on charcoal catalyst followed by reduction (of the cyano group) with sodium borohydride in the presence of cobalt(II) chloride to yield t-butyl p-(2-aminoethyl)-phenylpropionate. Condensation with 2-alpha,3-alpha-dihydroxy-4β-[9-(2-chloroadenyl)]-cyclopentane-1β-N-ethylcarboxamide yields the t-butyl ester of compound (a) which is hydrolyzed to compound (a) with aqueous hydrochloric acid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:5]=1[O:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O)([O-:3])=[O:2].C(Cl)Cl.O.NN.Cl>CO>[N+:1]([C:4]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:5]=1[O:6][NH2:7])([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 5 L four-necked flask equipped with an overhead stirrer, thermocouple and a condenser was charged with 2-(2,4-dinitrophenoxy)isoindoline-1,3-dione (I-36) (96 g, 291.6 mmol) and DCM (2 L). The stirred solution was cooled to 0° C. and a solution of hydrazine hydrate (36.46 g, 729 mol) in MeOH (300 mL) was added at 0° C. The reaction mixture rapidly became bright yellow and a precipitate formed. The suspension was stirred at 0° C. for 2 hours. 0.5 N HCl (2 L) was added at 0° C. and stirred for 30 minutes. The mixture was filtered and washed with DCM (2×200 mL). The organic layer was separated, dried over MgSO4, filtered and the solvent removed to give O-(2,4-dinitrophenyl)hydroxylamine (I-37) as a red-orange solid. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, 1 H), 8.44 (dd, 1 H), 8.07 (d, 1 H), 6.42 (sbr, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[N:5]2[N:6]=1.CC1NC2N(N=C(CCC)C=2)N=1>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:18][CH:19]=3)[N:5]2[N:6]=1
Reactant: CCCc1cc2nc(C)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCc1cc2[nH]c(C)nn2n1
Product: CCCc1cc2nc(C)nn2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A 1.66 g portion of the mixed product obtained in Example 1 consisting (about 3:1) of 2-methyl-6-propyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 1d) and 2-methyl-6-propyl-1H-pyrazolo[1,5-b][1,2,4]triazole was treated in the same manner as described in Example 12, the resulting residue was subjected to silica gel column chromatography. Elution was conducted with a gradient from chloroform only to methanol-chloroform (3:17, v/v) and then the eluted product was crystallized from ethyl acetate to give 0.44 g of 2-methyl-6-propyl-5-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole in the form of colorless crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]([C@@H:14]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C@H:18]([OH:25])[CH2:17][CH2:16][C@H:15]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33])=[N+:12]=[N-:13].C(N(CC)CC)C>ClCCl>[N:11]([C@@H:14]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[CH2:17][CH2:16][C@H:15]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: [N-]=[N+]=N[C@@H]1c2cccnc2C(=O)CC[C@H]1c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of oxalyl chloride (0.22 mL, 2.6 mmol) in dichloromethane (20 mL) at −15° C. was added DMSO (0.24 mL, 3.4 mmol). The reaction mixture was cooled to −78° C. and a solution of (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (prepared according to the procedures described in WO2011/046997, 270 mg, 0.85 mmol) in dichloromethane (5 mL) was added and the resulting solution was stirred at −78° C. for 2 h. Triethylamine (0.71 mL, 5.1 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and then washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc 100:0 to 0:100, to give the title compound. MS: m/z=315.2 (M+1).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1.N1C=CC=CC=1>ClC(Cl)C.ClCCl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][C:11]=1[CH3:16])=[O:4]
Reactant: Cc1cc(F)ccc1N
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(F)ccc1NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 9.1 g (0.05 mol) of trichloroacetyl chloride in 40 ml of dichloroethane is added at -5° C. to a solution of 6.25 g (0.05 mol) of 4-fluoro-2-methylaniline in 75 ml of dichloromethane and 3.95 g (0.05 mol) of pyridine. This solution is stirred at room temperature for one hour and then poured into ice-cold water, and the organic phase is separated after settling has taken place, washed with water and dried over sodium sulphate. It is filtered, the filtrate is evaporated and the residue is dispersed in hexane; a pink solid is thereby obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:34][CH2:33][C@:7]2([O:11][CH2:10][C@H:9]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([CH3:30])=[N:20][N:21](C(OC(C)(C)C)=O)[CH:22]=4)[CH:15]=[CH:14][C:13]=3[O:31][CH3:32])[CH2:8]2)[C@@H:6]1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:4].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:34][CH2:33][C@:7]2([O:11][CH2:10][C@H:9]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([CH3:30])=[N:20][NH:21][CH:22]=4)[CH:15]=[CH:14][C:13]=3[O:31][CH3:32])[CH2:8]2)[C@@H:6]1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3cc(-c4cn(C(=O)OC(C)(C)C)nc4C)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3cc(-c4c[nH]nc4C)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of (3S,5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(1-(tert-butoxycarbonyl)-3-methylpyrazol-4-yl)phenyl)-1-oxaspiro[4.4]nonane-7-carboxylic acid methyl ester (12 mg, 0.021 mmol) in 2.0 mL of dichloromethane was stirred at 0° C. and 2.0 mL of trifluoroacetic acid was added. After the solution had been stirred at 0° C. for 1.5 h, toluene (5 mL) was added and the solvent was evaporated at reduced pressure. The residue was purified by flash column chormatogrpahy on 1 g of silica gel, eluting with 25% ethyl acetate in dichloromethane to give 8 mg of colorless film (80% yield). 1H NMR (400 MHz, CDCl3): δ 7.60 (bs, 1H), 7.29 (dd, 2H, J=9, 6 Hz), 7.22 (dd, 1H, J=8, 2 Hz), 6.91 (d, 1H, J=8 Hz), 6.89 (t,,2H, J=9 Hz), 6.86 (d, 1H, J=2 Hz), 6.21 (t, 1H, J=2 Hz), 4.77 (dd, 1H, J=12, 2 Hz), 4.10 (dd, 1H, J=12, 2 Hz), 3.85 (s, 3H), 3.59 (s, 3H), 3.47 (dt, 1H, J=11, 8 Hz), 3.22 (d, 1H, J=11 Hz), 2.43-2.22 (m, 2H), 2.40 (s, 3H), 2.15-1.94 (m, 2H). Mass spectrum (NH3CI): m/e=436 M+1.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:15]=[CH:14][N:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:26]>CO>[ClH:26].[ClH:26].[ClH:26].[N:19]1([CH2:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cc(CN2CCCCC2)ccn1
Agent: Cl
Solvent: CO
Product: N=C(N)C(=N)NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The product of Step B (5.0 g; 13.7 mmoles) was dissolved in 80 ml of methanol and treated with 9.1 ml of concentrated HCl. After stirring at ambient temperature for 4.5 hours, the solution was evaporated to dryness under reduced pressure to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:30][CH2:31][CH3:32].[OH-].[Na+].Cl.CCOCC>CO.O>[O:29]=[C:24]1[CH2:25][CH2:26][CH2:27][C:28]2[C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[C:20]([CH2:30][CH2:31][CH3:32])[CH:21]=[CH:22][C:23]1=2
Reactant: CCCc1ccc2c(c1OCCCCCOc1ccccc1CCC(=O)OC)CCCC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCCc1ccc2c(c1OCCCCCOc1ccccc1CCC(=O)O)CCCC2=O
Yield: 100 %

Procedure:
The 2-[5-[(5-oxo-2-propyl-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]benzenepropanoic acid methyl ester from the preceding example (1.35 g; 2.99 mmol) and 8 mL of 1N aqueous sodium hydroxide in 15 mL of methanol was stirred and refluxed for 1.5 hr. After being cooled, the resulting solution was diluted with water and acidified with 3N HCl. Work-up with ether in the usual manner gave 1.3 g (100%) 2-[5-[(5-oxo-2-propyl-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]benzenepropanoic acid as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[BrH:18].C(N(CC)C1C=CC=CC=1)C.[N:30]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[BrH:18].[N:12]1([C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[NH:36])=[CH:3][CH:4]=2)=[O:11])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: N#CN1CCCC1
Reactant: Nc1ccc(CCC(=O)N2CCOCC2)cc1
Agent: Br
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: N=C(Nc1ccc(CCC(=O)N2CCOCC2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of step (b) (2.22 g, 0.00948 moles) was dissolved in 15 ml chlorobenzene. N,N-diethylaniline hydrobromide (2.18 g, 0.00948 moles) was added followed by 1-pyrrolidinecarbonitrile (1.37 g, 0.01422 moles). A catalytic amount of 4-dimethylaminopyridine was added and the reaction heated to reflux for 6 hours. The reaction was then cooled to room temperature and diluted with 100 ml ethyl acetate. A sticky oil precipitated from solution and was stirred for 24 hours. The resulting solids were filtered and recrystallized from hot isopropanol to give the N-(4-(2-((4-morpholinyl)carbonyl)ethyl)phenyl)-1-pyrrolidinecarboximidamide hydrobromide, M.P. 207°-209° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[CH2:16][CH2:15][CH2:14][CH:13]=1)=[O:11].[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:8][O:9][C:10]([C@:12]12[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:30][N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:25]2)=[O:11]
Reactant: COC(=O)C1=CCCC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@]12CCC[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 82.5 %

Procedure:
A catalytic amount of trifluoroacetic acid was added to a solution of 1-cyclopentene-1-carboxylic acid methyl ester (2.52 g, 20.0 mmol) and N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (5.00 g, 21.1 mmol) in dichloromethane (40 mL) at room temperature, and the mixture was heated with stirring at room temperature for 15.5 hours. The reaction solution was diluted with dichloromethane (100 mL) and washed with a saturated sodium bicarbonate solution (80 mL). The washed aqueous layer was further extracted with dichloromethane (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→90:10→80:20) to give 4.28 g (83%) of the title compound as a colorless transparent oil.
Reaction SMILES: C1([CH:7]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)C=CC=CC=1.C(=O)C1C=CC=CC=1>C(O)C>[CH:7]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][NH:11][CH:10]=[CH:9][N:8]=1
Reactant: c1ccc(C2NCCNCc3ccccc32)cc1
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: C1=CNCc2ccccc2C=N1

Procedure:
A mixture of 2 g (8.4 mmol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine and 1.0 g (9.2 mmol) of benzaldehyde in 40 mL of ethanol was refluxed for 30 min, cooled on ice and the product filtered off. There was obtained 2.33 g of 3,4-dihydro-1,11-diphenyl-2,5-methano-1,H, 6H-2,5-benzodiazocine, mp 175°-176°.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=O)[CH2:7][NH:8][C:9](=[O:34])[CH2:10][C:11]1[N:15](C(OC(C)(C)C)=O)[C:14]2[CH:23]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[C:26]([CH3:27])[C:13]=2[N:12]=1)C.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.O1CCCC1>[OH:5][C:6]1[CH2:7][NH:8][C:9](=[O:34])[C:10]=1[C:11]1[NH:15][C:14]2[CH:23]=[C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:25]=[C:26]([CH3:27])[C:13]=2[N:12]=1
Reactant: CCOC(=O)CNC(=O)Cc1nc2c(C)cc(N3CCOCC3)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)cc2[nH]c(C3=C(O)CNC3=O)nc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 8.7 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 0.003 g, 0.044 mmol) in toluene (1 mL) was added [2-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-acetylamino]-acetic acid ethyl ester (0.135 g, 0.293 mmol) in tetrahydrofuran (2 mL) over 5 minutes. The mixture was stirred at 90–100° C. for 5 hours, then cooled down to ˜0° C. and ethyl acetate followed by aqueous hydrochloric acid (1N, ˜0.5 mL) were added. The aqueous phase was washed with ethyl acetate (3×) and this was submitted to Prep HPLC (acetonitrile/ammonium acetate/water) to give the title material (0.008 g, 69%) as a white solid. HPLC 100% (220 nm); LCMS (+ESI, M+H+) m/z 315; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.55 (3H, s), 3.18 (4H, br dd), 3.81 (2H, s), 3.88 (4H, br dd), 6.92 (1H, br s), 6.99 (11H, d, J=2.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9](=[O:22])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C[CH:24]1[CH2:29][CH2:28][CH2:27][CH:26](C)N1.C(C1CC1)#C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH:28]1([C:27]#[C:26][C:2]2[CH:3]=[C:4]([C:9](=[O:22])[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=3)=[O:11])[CH:5]=[CH:6][C:7]=2[F:8])[CH2:29][CH2:24]1
Reactant: CC1CCCC(C)N1
Reactant: O=C(C(=O)c1ccc(F)c(Br)c1)c1ccc(OC(F)F)cc1
Agent: [Pd]
Agent: C#CC1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C(C(=O)c1ccc(F)c(C#CC2CC2)c1)c1ccc(OC(F)F)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(3-bromo-4-fluorophenyl)-2-[4-(difluoromethoxy)phenyl]ethane-1,2-dione (2.1 g, 5.63 mmol), 2,6-dimethylpiperidine (10 mL), and ethynylcyclopropane (0.74 g, 11.27 mmol) was degassed with argon for 5 minutes. Then, tetrakis(triphenylphosphine) palladium (0) (327 mg, 0.28 mmol) was added and the mixture was stirred at 80° C. for 5 hours. The mixture was poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by ICSO (hexane/EtOAc 5/1) gave 1-[3-(cyclopropylethynyl)-4-fluorophenyl]-2-[4-(difluoromethoxy)phenyl]ethane-1,2-dione as a yellow oil solid (1.37 g); MS m/e (M)+ 358.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:23][O:24][CH2:25][C@@H:26]([O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:32]1[CH2:33][CH2:34][CH:29]([O:28][C@@H:26]([CH3:27])[CH2:25][O:24][CH3:23])[CH2:30][CH2:31]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC[C@H](C)OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), (S)-4-(1-methoxypropan-2-yloxy)piperidine (92) (0.151 g, 0.87 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.280 g, 0.87 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.152 mL, 0.87 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam; (0.215 g, 70.7% yield) 1H NMR (400.132 MHz, CDCl3) δ 1.13 (3H, t), 1.61-1.49 (1H, m), 1.78-1.65 (2H, m), 1.91-1.87 (1H, m), 3.17-3.01 (1H, m), 3.31-3.27 (1H, m), 3.39-3.35 (4H, m), 3.57-3.45 (2H, m), 3.72-3.67 (2H, m), 4.06-3.97 (1H, m), 4.27 (2H, s), 7.01 (1H, t), 7.31-7.26 (2H, m), 7.79-7.70 (3H, m), 8.49-8.45 (1H, m), 10.50 (1H, s); m/z (LC-MS, ESI+), RT=1.81 (M+H 454).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[CH:9](=[O:13])[CH2:10][CH2:11][CH3:12].[N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[BH4-].[Na+].P([O-])([O-])([O-])=O>C(#N)C.C(OCC)(=O)C.CO>[C:16]1([NH:14][O:15][C@H:10]([CH2:11][CH3:12])[CH2:9][OH:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Nc1ccccc1
Reactant: CCCC=O
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC[C@H](CO)ONc1ccccc1
Temperature: -20 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
At about −20° C., L-proline (4 g, 34.8 mmol) was added to solution of n-butyraldehyde (25 mL, 278 mmol) and nitrosobenzene (15 g, 140 mmol) in acetonitrile (300 mL). The mixture was stirred at about −20° C. for about 48 hours, methanol (50 mL) and sodium borohydride (16 g, 432 mmol) were added, the mixture was stirred for about 10 minutes, and phosphate buffer was added. Following standard extractive workup with ethyl acetate, the crude product was purified by column chromatography with silica gel (petroleum ether-ethyl acetate =5:1, v:v, elution) to afford the title product (10.8 g, 43%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.01-6.96 (m, 3H), 3.90-3.74 (m, 3H), 1.75-1.57 (m, 2H), 1.02 (t, J=7.8 Hz, 3H); LC-MS: m/z=182 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[C:8](Cl)(=[O:10])[CH3:9].[OH-].[K+]>ClCCl>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: OCC1CCCN1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N1CCCC1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
2-(Hydroxymethyl)pyrrolidine (500 mg) was mixed with dichloromethane (5 ml), and TEA (0.9 ml) and acetyl chloride (407 mg) were added thereto at 0° C., followed by stirring at room temperature overnight. 8 M Potassium hydroxide was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted by the addition of water and CHCl3/MeOH (4:1), the organic layer was washed with water and saturated brine, and dried over anhydrous Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 1-[2-(hydroxymethyl)pyrrolidin-1-yl]ethanone (442 mg).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:18](Br)[CH:19]=[CH2:20].CCN(C(C)C)C(C)C.CO>CN(C=O)C.C(Cl)Cl>[CH2:20]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:19]=[CH2:18]
Reactant: CCCCCCCCNCCCCCCCC
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: C=CCN(CCCCCCCC)CCCCCCCC

Procedure:
Resin 3 (0.42 mmol g−1 (est.), 160 mg) in DMF (2 cm3) was treated with dioctylamine (1.7 mmol, 515 mm3) at 20° C. for 24 h. The resin was washed with DMF (10×5 cm3) and DCM (10 cm3), resuspended in DMF (2 cm3) and treated with allyl bromide (4.25 mmol, 365 mm3) at 20° C. for 24 h. The solvent and the reagent was then removed by filtration and the resin washed with DCM (2×20 cm3). The elimination was performed in DCM (4 cm3) with DIPEA (1.72 mmol, 300 mm3) over night. The filtrate of this last reaction step was combined with the DCM and MeOH wash (25 cm3) from the resin and evaporated. It gave 14 contaminated with DIPEA in 38 mg yield. The amine was transferred in little DCM (<0.5 cm3) to a K2CO3 covered dry silica column (5 g). Impurities were washed away with hexane and the amine eluted with ethyl acetate. After the removal of the solvent 14 (0.043 mmol, 12 mg, 64%) was obtained as a colourless oil. It was contaminated with 5% of 4 of a previous cycle.