Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]1[C:10]2[NH:11][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[C:21]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:20]([CH3:29])[C:19]4=[O:30])=[CH:13][C:9]=2[C:8](=[O:31])[NH:7]1)=[N+]=[N-].CP(C)C>C1COCC1.O>[NH2:1][CH2:4][CH2:5][C@@H:6]1[C:10]2[NH:11][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[C:21]([NH:24][C:25]([CH3:28])([CH3:26])[CH3:27])[N:20]([CH3:29])[C:19]4=[O:30])=[CH:13][C:9]=2[C:8](=[O:31])[NH:7]1
Reactant: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCN=[N+]=[N-])NC4=O)cccc2c1=O
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCN)NC4=O)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a solution of (R)-8-(6-(2-azidoethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrolo-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (504a, 200 mg, 0.476 mmol) in THF (7 mL) at RT was added trimethylphosphine (1.0 M in THF, 0.71 mL, 0.71 mmol) followed by 3 drops of water. It was stirred at RT for 30 min then the reaction mixture was concentrated and the crude residue was purified on the ISCO Combiflash RF (24 g Redisep column, using a gradient of 0-20% 2M NH3/MeOH in DCM) affording (R)-8-(6-(2-aminoethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (504, 65 mg, 0.166 mmol, 35% yield) as a light yellow amorphous solid after drying under vacuum. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.00 (1H, dd, J=8.0, 1.4 Hz), 7.93 (1H, dd, J=7.5, 1.5 Hz), 7.21 (1H, t, J=7.7 Hz), 6.75 (1H, s), 4.73 (1H, dd, J=7.6, 4.1 Hz), 3.56 (3H, s), 2.74-2.93 (2H, m), 2.12-2.26 (1H, m), 1.85-1.98 (1H, m), 1.57-1.67 (9H, s). m/z (ESI, +ve) 395.0 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:30])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)=[CH:14][CH:15]=2)[O:10][C:9](=[O:29])[CH:8]=1.C(CN)O>CN(C=O)C>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:30])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[O:10][C:9](=[O:29])[CH:8]=1
Reactant: O=C(Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12)NCCO
Solvent: CN(C)C=O
Solvent: NCCO
Product: O=C(Cc1cc(=O)oc2cc(O)ccc12)NCCO
Yield: 71.5 %

Procedure:
200 mg (0.85 mmole) of 7-hydroxycoumarin-4-methyl ester 2 (prepared as described in Scheme 1) was dissolved in 5 ml of dry DMF and stirred with 0.5 g (8.5 mmoles) of ethanolamine at room temperature for 52 hrs. The DMF was then evaporated from the dark brown solution. The residue obtained after further evaporation with methanol was dissolved in water and purified on a C-8 RP-HPLC column using a gradient of 5/95 CH3CN/water (0.1% TFA) to 30170 CH3CN/water (0.1% TFA) in 25.5 min. The peak eluting at 21.6 min was collected and lyophilized to give 0.16 g of an off-white powder MS: Mol. Formula, C13H13NO5 ; Calculated: 263.26, found (M+H)+ 264.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].C(C1NC=C[N+]=1C)C.Cl[C:26](=[O:31])[C:27]([O:29]C)=[O:28]>O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([F:1])=[C:3]2[C:11]([C:26](=[O:31])[C:27]([OH:29])=[O:28])=[CH:10][NH:9][C:4]=12
Reactant: Nc1ncc(F)c2cc[nH]c12
Reactant: COC(=O)C(=O)Cl
Agent: CCc1[nH]cc[n+]1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Nc1ncc(F)c2c(C(=O)C(=O)O)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-fluoro-1H-pyrrolo[2,3-c]pyridin-7-amine (2.26 g, 15 mmol) was added to a mixture of AlCl3 (12.0 g, 90.0 mmol) and ethylmethylimidazolium chloride (4.38 g, 30.0 mmol). Methyl chlorooxoacetate (3.6 mL, 30.0 mmol) was added slowly to the above solution and the mixture was stirred at rt for 3 h. Reaction flask was placed in an ice bath and water was slowly added until a white precipitate formed. The solid was collected by filtration and suspended in DMF. TEA (7 mL) was added and the mixture was stirred at rt for 1 h. Solvent was removed in vacuum. Chloroform (50 mL) was added and the solid was collected by filtration to afford 2-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid as a bright yellow solid (2.3 g, 90% pure). LCMS: m/e 238 (M+H)+, ret time 0.96 min (method 3).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>ClCCl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+3].[Rh+3]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a mixture of N-benzyloxycarbonyl-4-hydroxypiperidine (2.4 g, preparation described by Alig, L. et al (1992), J. Med. Chem. 35, 4393), dirhodium tetraacetate (40 mg) and dichloromethane (15 ml) under argon was added dropwise over 3-4 hours, with stirring, a solution of ethyl diazoacetate (1.2 ml) in dichloromethane (2.5 ml). On completion of the addition, the reaction mixture was stirred at ambient temperature overnight and then evaporated. The resultant oily residue was purified by column chromatography on silica eluting with 30% ethyl acetate/hexane to give ethyl N-(benzyloxycarbonyl)piperidin-4-yloxyacetate (2.4 g) as a colourless oil: NMR Spectrum (CDCl3) 1.20 (3H, t), 1.40 (2H, m), 1.82 (2H, m), 3.13 (2H, m), 3.57 (1H, m), 3.70 (2H, m), 4.11 (2H, q), 4.13 (2H, s), 5.07 (2H, s), 7.35 (5H, m); Mass Spectrum m/Z 322 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])N=N[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:26](N1CCCC1)=[CH2:27]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:27]=[CH:26][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)c(-c2ccc(CC)cc2)n1
Reactant: C=CN1CCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccc(CC)cc2)n1

Procedure:
Following General Procedure D, ethyl 5-(4-ethylphenyl)-6-phenyl-1,2,4-triazine-3-carboxylate (Compound 18, 245 mg, 0.74 mmol) and crude 1-vinylpyrrolidine (Compound 38, 572 mg) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([O:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:25])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-])=O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:25][C:16]1[CH:15]=[C:14]([O:13][C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([O:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH:5]=2)[CH:19]=[C:18]([F:20])[C:17]=1[C:21]([F:22])([F:24])[F:23]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)cc1[N+](=O)[O-]
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Oc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A mixture of 2-chloro-α,α,α,6-tetrafluoro-p-tolyl 3,4-dinitrophenyl ether (10.0 g, 0.026 mol), 4methoxyphenol (6.45 g, 0.052 mol) and potassium carbonate (7.26 g, 0.052 mol) in acetonitrile is refluxed for 18 hours, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an amber oil. Column chromatography of the oil using silica gel and a (1:4) ether/hexanes solution gives the title product as a yellow oil (3.0 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:7][CH:8]=[O:9])[CH2:3][C:4](O)=[O:5].S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[CH:7]=[CH:8][O:9][C:4](=[O:5])[CH2:3]1
Reactant: CC(C)(CC=O)CC(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1(C)C=COC(=O)C1

Procedure:
A solution of 1.05 g (7.28 mmol) of crude 3,3-dimethyl-5-oxopentanoic acid (from Example 8a) and 1 g (8.4 mmol) of thionyl chloride in 10 mL of benzene was heated under reflux for 62/3 hours. The reaction mixture was concentrated to give 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)cc1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.1) (0.44 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 1.0 mmol) according to the general procedure VI. Obtained as a yellow solid (0.031 g, 7%). MS (ISP) 451.0 [(M+H)+]; mp 286° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:23].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]1[S:23][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: Fc1cncc(F)c1N=C(Cl)c1c(Cl)cc(I)cc1Cl
Reactant: NC(N)=S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Fc1cncc2sc(-c3c(Cl)cc(I)cc3Cl)nc12
Temperature: 70 °C
Yield: 65.7 %

Procedure:
A suspension of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-4-iodobenzimidoyl chloride (8.8 g, 19.7 mmol), thiourea (6.0 g, 78.8 mol) and pyridine (5.4 mL, 66.9 mmol) in isopropanol (80 mL), under a nitrogen atmosphere, was heated under reflux for 6 hours. After this time, the reaction mixture was cooled to 70° C. and Et3N (16.4 mL, 118.1 mmol) was added over 5 minutes and then the resultant mixture was heated under reflux for a further 18 hours. Upon cooling to room temperature, the precipitate obtained was collected by filtration and the filtrate was then partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were dried (MgSO4), filtered and concentrated to dryness to afford the title compound as an off-white solid (5.5 g, 66% yield). LCMS (Method D): RT=4.22 min, m/z: 426 [M+H+].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[O:34]>ClCCl>[CH3:39][O:38][CH2:37][CH2:36][O:35][C:33]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1)=[O:34]
Reactant: COCCOC(=O)Cl
Reactant: N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCOC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reaction time: 4 h
Yield: 78.1 %

Procedure:
(5R)-3-(4-((3R)-3-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (200 mg, 0.52 mM) was suspended by stirring in dichloromethane (10 ml) at 0° and sodium bicarbonate solution (5 ml) added. 2-Methoxyethyl chloroformate (340 mg, 2.46 mM) was added, and the mixture stirred 4 hours, allowing the temperature to rise to ambient. The organic layer was separated, washed with sodium dihydrogen phosphate (2%, 2×15 ml), water (15 ml) and dried (magnesium sulfate). Filtration and evaporation gave the desired product (183 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15](Br)=[CH:16][C:10]=2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:10]=2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(Br)cc2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCc2sc(-c3ccccc3)cc2C1

Procedure:
A solution of N-Boc-2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Step 1; 637 mg, 0.2 mmol), phenyl boronic acid (244 mg, 0.2 mmol), NaHCO3 (504 mg, 6 mmol) and tetrakis(triphenylphosphine)palladium(O) (116 mg, 0.1 mmol) in DME (10 mL) and water (10 mL) was heated to 80° C. for 20 h. The mixture was partitioned between water and EtOAc, washed with aqueous NaHCO3, water (2×) then brine, dried and evaporated. Column chromatography of the residue (silica gel; hexane/EtOAc 95:5) afforded the title compound as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:29][CH2:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: COc1ccccc1CCN
Product: COc1ccccc1CCNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[2-(2-methoxyphenyl)ethyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.54 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.81 mmol of 2-(2-methoxy-phenyl)-ethylamine. LC/MS [10.19 min; 492 (M+1)]
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:35]=[CH:34][C:14]2[C@@H:15]3[C@H:20]([CH2:21][CH2:22][C:13]=2[CH:12]=1)[N:19]([C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)=[O:24])[CH2:18][CH2:17][CH2:16]3)=O.O>O1CCCC1>[NH:29]1[C:28]2[CH:32]=[CH:33][C:25]([C:23]([N:19]3[C@@H:20]4[C@@H:15]([C:14]5[CH:34]=[CH:35][C:11]([CH2:9][OH:8])=[CH:12][C:13]=5[CH2:22][CH2:21]4)[CH2:16][CH2:17][CH2:18]3)=[O:24])=[CH:26][C:27]=2[N:31]=[CH:30]1
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(CO)cc3CC[C@@H]21
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (1 mol/L in tetrahydrofuran, 0.5 mL) is added to a solution of cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester (150 mg) in tetrahydrofuran (6 mL) cooled to −10° C. The resulting solution is stirred for 2 h while warming to ca. −3° C. in the cooling bath. Little water is added carefully and the resulting mixture is filtered over Celite. The filtrate is diluted with ethyl acetate and dried (MgSO4). The solvent is evaporated and the residue is triturated with ethyl acetate and dried to give the title compound as a solid. Yield: 56 mg (40% of theory); LC (method 1): tR=2.03 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21].[NH:22]1[C:30]2[C:25](=CC=C[CH:29]=2)[C:24]2(COC3C=C4C(=[CH:41][C:31]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.BrCC1CCCCO1>>[N:22]1[CH:41]=[CH:31][CH:24]=[CH:25][C:30]=1[CH2:29][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCC3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Br
Agent: BrCC1CCCCO1
Agent: BrCc1ccccn1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCC3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 198-200° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (d, J=4.8 Hz, 1H), 7.71 (dd, J=7.8, 7.5 Hz, 1H), 7.32-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.82 (s, 1H), 6.17 (s, 1H), 5.27 (d, J=15.6 Hz, 1H), 5.01 (d, J=15.6 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.49 (td, J=8.7, 0.7 Hz, 2H), 3.15 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.3, 155.2, 154.9, 148.6, 142.1, 138.3, 132.1, 129.1, 128.9, 127.6, 124.0, 123.7, 123.3, 122.3, 109.7, 107.2, 104.0, 80.1, 71.8, 58.6, 45.5, 30.4; MS (ES+) m/z 370.9 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]12([NH:21][C:22](=[O:40])[C:23]([CH2:38][OH:39])([CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(N(CC)CC)C>C(Cl)Cl>[C:11]12([NH:21][C:22](=[O:40])[C:23]([CH:38]=[O:39])([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH2:12][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:19]3)[CH2:18]1)[CH2:20]2
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(CO)(Cc1ccncc1)Cc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 163.3 %

Procedure:
To a well-stirred dry ice/acetone bath chilled solution of oxalyl chloride (163,μl, 1.91 mmol) in methylene chloride (4.5 ml), a solution of dimethyl sulfoxide (259 μl, 3.6 mmol) in methylene chloride (2.25 ml) was added dropwise while maintaining the temperature below -55° C. After stirring the reaction at that temperature for 5 minutes, N-adamantan-1-yl-2-hydroxymethyl-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propion-amide (700 mg, 1.73 mmol) in methylene chloride (2.25 ml) was added, and the reaction was stirred for 30 minutes. Triethylamine (1.20 ml, 8.65 mmol) was added, and the reaction was stirred for 5 minutes before removing the cooling bath. After stirring for 20 minutes at ambient temperature, the reaction was quenched by addition to water/methylene chloride (40 ml of each). The mixture was then extracted three times with 40 ml portions of methylene chloride. The combined extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to afford a yellow oil (1.14 g). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution initially with methanol/methylene chloride=3:97 in volume, and increasing the methanol concentration during elution finally to methanol/methylene chloride=1:9 in volume) afforded the title compound (475 mg) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:13][CH2:12][CH2:11][C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10]=2[O:9][CH:8]=1
Reactant: OCCc1coc2c(O)cccc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c(CCO)coc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
7-hydroxy-3-(2-hydroxyethyl)benzofuran (1.09 g), methyl bromoacetate (0.86 ml) and potassium carbonate (930 mg) were added to DMF (50 ml) and the mixture was stirred at room temperature for 18 hours. After filtering the reaction solution, the filtrate was concentrated and added to water layer (150 ml), followed by extracting the resultant twice with ethyl acetate (20 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1) using silica gel to obtain the desired compound (1.48 g, yield: 97%).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[OH-].[Na+].Cl>O.CCO.C(OCC)C>[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N:2][OH:3])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: NO
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydroxylamine hydrochloride (4.65 g, 67.4 mmol) was slowly added to a solution of 4-tert-butylbenzaldehyde (10 g, 61.6 mmol) in water (34 ml) and EtOH (7 ml). An aqueous solution of sodium hydroxide (3.6 g, 153 mmol) was slowly added dropwise, so the temperature of the reaction mixture did not exceed 25° C. The reaction mixture was stirred overnight at RT and mixed with diethyl ether. The aqueous phase was neutralised with 0.5 M aq. hydrochloric acid solution and extracted several times with ether. The combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. The desired product 4-tert-butylbenzaldehyde oxime was obtained in a yield of 84% of the theoretical amount (9.1 g)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=5)=[O:22])[CH2:17]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:11][CH2:12][CH:13]([N:16]4[CH2:17][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=5)=[O:22])[CH2:19]4)[CH2:14][CH2:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
A solution of N-{[1-(4-Benzo[1,3]dioxol-5-yl-cyclohex-3-enyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide (as prepared in the previous step, 250 mg, 0.5 mmol) in MeOH (20 mL) was driven through an H-Cube® Continuous-flow Hydrogenation reactor (ThalesNano, Budapest, Hungary) under full hydrogen mode at room temperature using a 5% Pd/C cartridge. The resulting solution was concentrated and purified by silica gel column on a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the two title compounds as white solids.