Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(N2CC[N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=CC=[CH:17][CH:16]=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.CC1OC(CN)=CC=1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:9][CH2:12][C:13]4[O:14][C:15]([CH3:20])=[CH:16][CH:17]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1ccc(CN)o1
Product: Cc1ccc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)o1
Yield: 78 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-methylfuran-2-yl)methanamine, the title compound was obtained as a yellowish solid in 78% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.08-6.98 (m, 2H), 6.12 (d, J=2.4 Hz, 1H), 6.07 (s, 1H), 5.93 (t, J=4.8 Hz, 1H), 5.89 (d, J=2.4 Hz, 1H), 4.49 (d, J=4.8 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.49-3.39 (m, 2H), 2.48 (s, 3H), 2.27 (s, 3H); MS (ES+) m/z 450.1 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C1C(=O)N([Br:24])C(=O)C1.C(Cl)Cl.O>CC#N.CC(N=NC(C#N)(C)C)(C#N)C>[Br:24][CH2:13][C:6]1[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1CBr
Temperature: 70 °C
Yield: 31.4 %

Procedure:
A mixture of methyl 5-methoxy-2-methyl-4-nitrobenzoate (1.11 g, 5 mmol) and NBS (1.07 g, 6 mmol) in MeCN (20 mL) was degassed and then AIBN (18 mg, 0.11 mmol) was added. The mixture was heated to 70° C. for 18 h. DCM (50 mL) and water (50 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) in order to remove baseline impurities gave methyl 2-(bromomethyl)-5-methoxy-4-nitrobenzoate (477 mg, 31%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M−Br]−=224 at 3.92 min. 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.66 (s, 1H), 4.88 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([O:9][C:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.N[CH:20]1[CH:25]2CCN(C[CH2:24]2)[CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]1([CH:7]([O:9][C:10](=[O:11])[NH:12][CH:16]2[CH:25]3[CH2:24][CH2:13][N:14]([CH2:21][CH2:20]3)[CH2:15]2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(OC(=O)n1ccnc1)c1ccccc1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OC(=O)NC1CN2CCC1CC2)c1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of imidazole-1-carboxylic acid 1-phenyl-ethyl ester 0.50 g (2.31 mmol) in 5 ml dimethylformamide, 3-aminoquinuclidine dihydrochloride 0.46 g (2.31 mmol) and sodium carbonate 0.49 g (4.62 mmol) are added. The suspension is heated up to 80° C. and stirred for 18 hours at this temperature. The reaction mixture is then cooled and extracted with water and ethylacetate. The combined organic phases are dried and evaporated. The oily residue is dried, dissolved in ether and acidified with a 4 M hydrochloric acid dioxane solution. The precipitating crystals are filtered, washed with ether and dried to give the title product. Mp=71-72° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](=O)[CH2:7][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[F:1][C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1CC(=O)S2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(F)c2sccc12
Temperature: 35 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 7-fluoro-4-methoxy-1-benzothiophen-2(3H)-one (1.06, 5.4 mmol) in dichloromethane (10 mL) at 0° C. was added slowly a solution of diisobutylaluminium hydride in dichloromethane (1 M, 8.04 mL, 8.0 mmol). After 30 mins the reaction was quenched by careful addition of aqueous hydrochloric acid (6 N, 25 mL). The mixture was concentrated to remove the dichloromethane, the aqueous residue was then stirred at 35° C. for 2 h. The aqueous solution was extracted with diethyl ether (3×50 mL), washed with aqueous sodium hydroxide (2 N, 50 mL), brine (50 mL) then dried (MgSO4) and the solvent evaporated in vacuo to give the title compound (0.86 g, 87%) as a purple oil; δH 7.44-7.38 (1H, m, ArH), 7.36-7.24 (1H, m, ArH), 6.88-6.80 (1H, m, ArH), 6.57-6.49 (1H, m, ArH) and 3.82 (3H, s, OCH3).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH3:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C(Cl)Cl>[CH3:24][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:12]([O:11][CH3:10])[C:13]=1[C:14]([NH:16][C:17]([NH:4][C:3]1[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[F:9])=[O:18])=[O:15]
Reactant: Nc1c(F)cccc1F
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 60 g. portion of 2,6-difluoroaniline was dissolved in 1500 ml. methylene chloride and cooled to 10° C. Under a nitrogen atmosphere, 90 g. of 2,6-dimethoxybenzoylisocyanate in 200 ml. methylene chloride was added dropwise. The mixture was allowed to stir at 25° C. for three hours. The solid was collected and washed with water. The filtrate was evaporated to dryness, and 150 ml. diethyl ether and 150 ml. ethanol were added. The solid was again collected. Yield 89.0 g. (60%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]>C(O)C>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
A mixture of piperazine (0.86 g), the above ester (1.0 g) and ethanol (20 ml) was refluxed for 2.5 hrs. The solvent was evaporated, and the residue was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and chloroform was evaporated. The residue was purified by chromatography to give 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([N:22]=[CH:23][N:24]([CH3:26])[CH3:25])(=[O:21])=[O:20])[CH:13]=2)=[O:11])=[C:8]([Cl:29])[C:7]=1[Cl:30].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([N:22]=[CH:23][N:24]([CH3:26])[CH3:25])(=[O:20])=[O:21])[CH:13]=2)=[O:11])=[C:8]([Cl:29])[C:7]=1[Cl:30])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2ccc(O)c(Cl)c2Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.6 g (40 mmol) of allyl bromide are added dropwise, with magnetic stirring, to a mixture of 13.1 g (30 mmol) of 4-hydroxy-3'-dimethylaminomethyleneaminosulfonyl-2,3,4'-trichlorobenzophenone, 5.0 g (36 mmol) of ground potassium carbonate and 50 ml of dry dimethylformamide at room temperature, and the mixture is stirred for about 8 hours. The pale yellow suspension is then stirred in portions into a mixture of 400 ml of ice-water and 100 ml of 2N hydrochloric acid, and the precipitate is filtered off. Colorless crystals, melting point 141°-142° C. (from acetone/ethanol).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH:10]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11]1>O1CCOCC1.C(#N)C>[CH:10]1([NH:13][C:14]([N:6]2[CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:5]2)=[O:15])[CH2:12][CH2:11]1
Reactant: O=C=NC1CC1
Reactant: c1nc2c([nH]1)CCNC2
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(NC1CC1)N1CCc2[nH]cnc2C1
Yield: 34.3 %

Procedure:
A solution of 3.69 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 7.47 g of cyclopropyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. After evaporation to dryness, the residue is dissolved in 44 ml of methanol and treated with 11 ml of 2N sodium hydroxide for 1.5 h at room temperature. After neutralization, the solution is extracted with chloroform. Evaporation of the solvent leaves a residue that is taken up in acetonitrile to give 2.12 g of the title compound, m.p. 215°.
Reaction SMILES: N.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[S:18]>C(Cl)Cl.CCCCCC>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([N:13]=[C:17]=[S:18])[CH:14]=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: N
Solvent: ClCCl
Solvent: CCCCCC
Product: S=C=Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
The final product, Compound 1 is obtained by treatment of Z with thiocarbonyl di-imidazole followed by ammonia. 3-Benzyloxyaniline (5 g, 25 mmol) is added dropwise over a one minute period to 4.94 g (27.6 mmol) thiocabonyl di-imidazole in methylene chloride (150 ml). The resulting mixture is stirred at room temperature overnight. An additional 400 mg thiocarbonyl di-imidazole (TCDI) is added and the reaction is continued for 2 hours more. The reaction is diluted with hexane and filtered through silica. Concentration provides 5.1 g of the desired 3-benzyloxyphenyl isothiocyanate.
Reaction SMILES: C([O:4][C:5]([C:7]1([C:18]2([NH:21][C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27]C)=[O:25])[CH2:20][CH2:19]2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=O)(C)C.[Na]>C1(C)C=CC=CC=1.CO>[CH3:27][O:26][C:24]([CH:23]1[C:22](=[O:29])[NH:21][C:18]2([CH2:19][CH2:20]2)[C:7]2([CH2:8][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:10]2)[C:5]1=[O:4])=[O:25]
Reactant: CCOC(=O)CC(=O)NC1(C2(C(=O)OC(C)C)CN(C(=O)OC(C)(C)C)C2)CC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1C(=O)NC2(CC2)C2(CN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 85 °C

Procedure:
The mixture of 3-[1-(2-ethoxycarbonyl-acetylamino)-cyclopropyl]-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-isopropyl ester and ethyl ester (Example 180b) (350 mg; 0.35 mmol) is dissolved in toluene (5 ml) and added dropwise under stirring to a solution of sodium (20 mg; 0.85 mol) in MeOH (1 ml). The mixture is heated to 85° C. for 45 minutes, cooled, and the resulting suspension (Na-salt of title compound) filtered, washed with toluene and isopentane. The white solid is taken up in water/2N HCl (20 ml/0.5 ml) and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to deliver the title compound as almost colorless foam (166 mg; 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Reactant: c1ccccc1
Solvent: O
Product: O=C(c1ccccc1)c1ccc(F)c(Cl)c1

Procedure:
3-chloro-4-fluorobenzoyl chloride (1.0 g), benzene (2 ml) and ferric chloride (0.28 g) were heated to reflux for 16 h then diluted with water, extracted with ethyl acetate and the organics dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound as a brown solid (0.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.OC1C=CC(C(O)=O)=CC=1.[Na+].[I-:26].[OH-].[Na+].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].Cl>CO>[I:26][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: [I-]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cl
Agent: O=C(O)c1ccc(O)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: CO
Product: O=C(O)c1ccc2c(I)c(O)ccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Mono-iodination of 6-hydroxy-2-naphthoic acid and 4-hydroxybenzoic acid was carried out following the procedure of Edgar and Falling (J. Org. Chem. 55, 5287, 1990). Thus, 0.75 gm of (4.34 mmol) was dissolved in 19 ml of MeOH and 1.04 gm of NaI (and 0.27 gm of NaOH was added. The solution was cooled to 0° C. and aqueous NaOCl (4% solution, 12.9 ml) was added dropwise over 75 min. The resulting mixture was stirred for 1 hr at 0° C. and then treated with 7 ml of 10% aqueous sodium metabisulfite. The mixture was adjusted to pH 7 using 5% HCl and extracted with 40 ml of ether. The organic layer was washed with brine and dried over MgSO4. The solution was concentrated to an off-white solid, that was recrystallized from toluene/CH3OH to provide 0.42 gm of 5-iodo-6-hydroxy-2-naphthoic acid. Reaction of 6′-Tostylatractyloside with 1,2-ethylenediamine
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:23])[CH:11]=[C:12](C(O)=O)[N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:23])[CH:11]=[CH:12][N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)cn1CC(F)(F)F
Solvent: CN(C)C=O
Product: O=c1ccn(CC(F)(F)F)cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
5-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (10.5 g, 42.7 mmol) was dissolved in sodium hydroxide solution (1.71 g, 42.7 mmol in 77 mL de-ionized water). 2,2,2-Trifluoroethylamine hydrochloride (23.1 g, 171 mmol) was added and the resulting suspension was stirred at 70° C. (oil-bath temperature) in the sealed flask for 17 hours. The reaction mixture was then filtered and the off-white solid was washed with de-ionized water (20 mL×5) to give 5-(benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (6.00 g). Yield=43%; 1H NMR (MeOD-D4, 90 MHz) δ 7.30 (s, 1H), 6.76-7.09 (m, 5H), 6.71 (s, 1H), 4.93 (d, J=8.4 Hz, 2H) and 4.65 (s, 2H); MS m/z 328 [M+1]+. (b) 5-(Benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (4.70 g, 14.4 mmol) was mixed with DMF (25 mL) and heated to 130° C. (bath temperature) for 3 hours. The mixture was concentrated under reduced pressure using a rotary evaporator and the residue was mixed with ethyl acetate (50 mL). It was then stirred for 2 hours at room temperature and filtered. The filtrate was concentrated to give 3-(benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (3.58 g). Yield=69%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.57-7.84 (m, 2H), 7.22-7.57 (m, 5H), 6.25 (br. s, 1H) and 4.69-5.28 (m, 4H); MS m/z 284 [M+1]+. (c) 3-(Benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (1.2 g, 4.2 mmol) was mixed with 10% Palladium on charcoal (wet, 0.12 g) in ethanol (70 mL). The resulting mixture was hydrogenated at 15 psi of hydrogen pressure for 1.5 hours. Palladium was removed by filtration through a layer of Celite™ and the Celite™ cake was washed with methanol (5 mL×3). The filtrate was evaporated to give 3-hydroxy-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (0.78 g) as white solid. Yield=95%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.60 (d, J=7.1 Hz, 1H), 7.46 (s, 1H), 6.23 (d, J=7.1 Hz, 1H) and 4.80-5.00 (m, 2H); MS m/z 194 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]>CCOC(C)=O.C(O)C.[Pt]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[NH2:8]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1Cl
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOc1ccc(N)cc1Cl
Reaction time: 16 h
Yield: 97.6 %

Procedure:
2-Chloro-1-{[2-(methyloxy)ethyl]oxy}-4-nitrobenzene (1.0 g) was dissolved in a 1:1 solution of EtOAc and ethanol (30 mL). Pt/C (0.15 g of 10% by weight) was added and the resulting mixture was placed under 50 psi of H2 for 16 h. The reaction was then filtered through celite and the resulting organics were concentrated in vacuo to obtain 0.85 g of the compound. 1H NMR (300 MHz, DMSO-d6): δ 6.88 (d, 1H), 6.66 (m, 1H), 6.50 (m, 1H), 4.00 (m, 2H), 3.63 (m, 2H), 3.33 (s, 3H).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].Cl[SiH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>>[CH:3]([Si@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2][CH3:1]
Reactant: CCCc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1
Reactant: C=CCCl
Product: CC=C[Si@H]1CC[C@H](c2ccc(-c3ccc(CCC)cc3)cc2)CC1

Procedure:
Preparation was conducted in the same manner as in Example 1 except for the fact that allyl chloride was used instead of n-propylbromide and that 4'-(4-chloro-4-silacyclohexyl)-4-n-propylbiphenyl was used instead of 4'-(4-chloro-4-silacyclohexyl)-4-fluorobiphenyl.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][O:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:23]2[CH2:24][CH2:25][C:20]3([CH2:17][O:18][CH2:19]3)[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: C1CC2(CCN1)COC2
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCC3(CC2)COC3)cc1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of 4-bromobenzyl bromide (0.26 g, 1.04 mmol), triethylamine (0.21 mL, 2.07 mmol) and 2-oxa-7-azaspiro[3.5]nonane (0.50 g, 2.07 mmol) in THF (20 mL) was heated under reflux for 5 h. The reaction mixture was cooled to ambient temperature, the solid removed by filtration and the filtrate was concentrated under reduced pressure. The resultant residue was loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia in MeOH to afford the title compound (0.30 g, 97%). 1H NMR (CDCl3, 300 MHz): 7.47-7.41 (m, 2H), 7.19 (d, J=8.1 Hz, 2H), 4.40 (s, 4H), 3.45-3.40 (m, 2H), 2.38-2.28 (s, 2H), 1.92-1.86 (s, 4H). LCMS (Method B): RT=1.89 min, M+H+=296/298.
Reaction SMILES: N1CCC(C2C3C(=CC=CC=3)NC=2)CC1.C(OC(C1OC(C[Br:27])=CC=1)=O)C.[F:28][C:29]1[CH:59]=[CH:58][C:32]([CH2:33]N2C3C(=CC=CC=3)C(C3CCN(CC4OC(C(O)=O)=CC=4)CC3)=C2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:59]=[CH:58][C:32]([CH2:33][Br:27])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(CN2CCC(c3cn(Cc4ccc(F)cc4)c4ccccc34)CC2)o1
Reactant: CCOC(=O)c1ccc(CBr)o1
Agent: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: Fc1ccc(CBr)cc1
Yield: 32 %

Procedure:
The procedure described in Example 1 was performed using 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.19 g (1.1 mmol) of 5-bromomethyl-furan-2-carboxylic acid ethyl ester. 0.08 g (0.22 mmol) of the crude, obtained as in step D, were then alkylated with 0.04 mL (0.33 mmol) of 4-fluorobenzyl bromide affording 0.031 g (32% yield) of 5-{4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-piperidin-1-ylmethyl}-furan-2-carboxylic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])(=[O:3])[CH3:2].[O-:18][O-:19].[Na+].[Na+]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:18][O:19][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:16])(=[O:3])[CH3:2]
Reactant: [O-][O-]
Reactant: CC(=O)OCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Product: CC(=O)OCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCOC(C)=O
Temperature: 0 °C

Procedure:
In 50 ml of petroleum ether was dissolved 10.5 g of 11-acetoxyundecanoylchloride. To the solution was added 20 ml of ice-water. To the mixture was further added, while stirring, 4 g of sodium peroxide little by little. The organic layer was separated, and the aqueous layer was subjected to extraction with ether. The organic layer and the ether extracts were combined, washed with water and dried, followed by evaporation of the solvent to yield 8.6 g of white wax-like bis(11-acetoxyundecanoyl)peroxide.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.Br[CH2:33][CH3:34].C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH2:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH3:34]
Reactant: CCBr
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 50 mg (0.12 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo [1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 20 mL CH3CN was treated with 26 mg (0.24 mmol) bromoethane and 33 mg (0.24 mmol) K2CO3. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 50 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, obtained the title compound in 20 mg as a yellow solid. MS (ES+): 440 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31](Cl)[N:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([NH:25][C@H:23]([C:14]2[N:13]([C@H:11]3[CH2:12][C@H:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:10]3)[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=2)[CH3:24])[N:30]=[CH:29][N:28]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 90 °C

Procedure:
A mixture of (S)-1-[1-(trans-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (67 mg, 0.20 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (31 mg, 0.20 mmol) and DIPEA (0.18 mL, 0.99 mmol) in IPA (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM then MeOH and then 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford the title compound as a colourless glassy solid (60 mg, 67%). LCMS (Method B): RT 3.09 min [M+H]+ 458