Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]([CH3:19])[C:6]2[O:11][C:10]([CH2:13][C:14](O)=[O:15])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:17]=1[CH3:18].S(Cl)([Cl:23])=O>CN(C)C=O.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]([CH3:19])[C:6]2[O:11][C:10]([CH2:13][C:14]([Cl:23])=[O:15])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:17]=1[CH3:18]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2

Procedure:
To a solution composed of 3.34 g of (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetic acid, 2 drops of N,N-dimethylformamide and 50 ml of benzene was added 0.87 ml of thionyl chloride, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. The above procedure gave (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetyl chloride in a quantitative yield of 3.56 g.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(OCc1ccccc1)c1ccc(O)nc1
Temperature: 0 °C

Procedure:
30 g of 6-hydroxynicotinic acid were treated with 500 ml of benzyl alcohol and 1 ml of concentrated sulfuric acid. After boiling at reflux for 3 days, the reaction mixture was poured on to ice-water, extracted several times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated, firstly in a water-jet vacuum and then in a high vacuum. The semi-crystalline residue was filtered over silica gel (eluent hexane/ethyl acetate=2:1, then ethyl acetate) and recrystallized from ethyl acetate/hexane. There were obtained 19 g of benzyl 6-hydroxy-nicotinate in colourless crystals, m.p. 178-179° C.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]=[O:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>CS(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22])[CH:9]=[C:8]2[CH:14]=[O:15]
Reactant: ClCCCCCBr
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)c(C=O)cn2CCCCCCl
Reaction time: 0.5 h

Procedure:
To a stirred mixture of powdered potassium hydroxide in methyl sulfoxide is added dropwise a solution of 5-methoxyindole-3-carboxaldehyde in methyl sulfoxide. The mixture is stirred for 30 min and 1-bromo-5-chloropentane is added dropwise. The mixture is stirred for 1 h and partitioned between ethyl acetate and water. The combined organic extracts are washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: ClC1C=C([C@H]2OC(=O)N([C@H](C)C[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)C2)C=CC=1.Br[CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:22]1[C:19]2[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=2[O:23][C:26]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: C[C@H](Cc1ccc(O)c(O)c1)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccccc2O1
Reaction time: 8 h

Procedure:
A mixture of 240 mg of the above oxazolidinone, 234 mg of diethyl bromomalonate, 450 mg of anhydrous potassium carbonate and 10 ml of acetone is stirred overnight, filtered, washed with acetone and evaporated to a brown oil. The oil is purified by flash chromatography, eluting with 5 percent acetone in toluene. The pure fractions are combined and evaporated giving 237 mg of (R,R)-5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([F:13])[CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CCO.[OH-].[Pd+2].[OH-]>[F:13][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:12]=[CH:11][N:10]=1
Reactant: [H][H]
Reactant: Fc1cc(C2=CCOCC2)ccn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Fc1cc(C2CCOCC2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A suspension of palladium hydroxide, (20 wt % palladium dry basis on carbon, wet, degussa type e101 ne/w, 150 mg), and 4-(3,6-Dihydro-2H-pyran-4-yl)-2-fluoropyridine (0.90 g, 5.0 mmol) in EtOH (10 mL) was placed under 1 atm hydrogen (balloon) and stirred for 4 h at RT. The mixture was then placed back under argon atmosphere, the palladium was filtered off, and the filtrate was concentrated to give 2-fluoro-4-(tetrahydro-2H-pyran-4-yl)pyridine (0.86 g, 4.76 mmol, 95%) as a yellow oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[C:1]([NH:8][C@H:9]([C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N1CCOCC1
Yield: 95 %

Procedure:
In substantially the same manner as in Example 5, morpholine (280 μl) was condensed with Boc-L-homophenylalanine (900 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-(BOC-L-homophenylalanyl)morpholine (1.06 g) as a white powder (yield 95%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (338 mg) as obtained in Reference Example 8 to yield the title compound (compound 65; 630 mg) as a white powder (yield 77%).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.S(Cl)([Cl:15])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH2:1][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CCl)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 235 g of veratryl alcohol in 1.4 liters of dry methylene chloride, 200 g of thionyl chloride was added dropwise while cooling with ice, and the mixture was stirred at room temperature overnight. The resulting dark brown reaction solution was poured into one liter of ice water. The pH of the solution was adjusted to 7.0 with sodium bicarbonate. The methylene chloride layer was separated, washed with water, dehydrated, and concentrated to dryness under vacuum to obtain 220 g of 3,4-dimethoxybenzyl chloride having a melting point of 50° to 51° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:16][CH2:17][C:18]#[N:19]>Cl.O1CCOCC1>[Cl:16][CH2:17][C:18]1[NH:19][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: N#CCCl
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(CCl)nc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (1.70 g, 8.1 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (20 mL) was added chloroacetonitrile (0.88 mL, 14 mmol). The reaction mixture was heated to 50° C. and stirred for 3 h. The mixture was then cooled to rt, concentrated and the residue was twice co-evaporated with toluene. Water was added and the solid was filtered to afford methyl 2-(chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (1.8 g, 88%). LC-MS: (FA) ES+ 253; 1H NMR (400 MHz, DMSO) δ 12.81 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 8.14 (d, J=1.1 Hz, 1H), 8.02 (dd, J=8.2, 1.6 Hz, 1H), 4.57 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:26])[C:21]2[CH:20]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:19]3[O:18][C:17]=2[CH2:16][CH2:15][CH2:14]1.[C:27](=O)([O:30]C)[O:28][CH3:29]>O1CCCC1>[O:26]=[C:13]1[C:21]2[CH:20]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:19]3[O:18][C:17]=2[CH2:16][CH2:15][CH:14]1[C:27]([O:28][CH3:29])=[O:30]
Reactant: O=C1CCCC2=C1C1CCCCC1O2
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1CCC2=C(C1=O)C1CCCCC1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.56 mL, 39.0 mmol) in tetrahydrofuran (20 mL) was cooled to −78° C. and then treated with n-butyllithium (15.60 mL, 39.0 mmol) added dropwise. The mixture was stirred at this temperature for 30 minutes. The solution was transferred by cannula needle into a solution of the product from Example 1A, (3,4,5a,6,7,8,9,9a-octahydrodibenzo[b,d]furan-1(2H)-one, 2.5 g, 13.00 mmol) in tetrahydrofuran (40 mL) precooled to −78° C., and the resulting mixture was stirred for 30 minutes at −78° C. Then, dimethyl carbonate (11.71 g, 130 mmol) was added and the dry ice bath was removed. The mixture was stirred and allowed to warm to ambient temperature with stirring continued for 16 hours. The mixture was quenched with hydrochloric acid (1N, 40 mL) and diluted with ether (200 mL). The organic layer was separated and the aqueous layer was extracted with additional ether. The organic layers were combined and washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 10-30% ethyl acetate in hexanes to provide the title product: 1H NMR (CDCl3) δ 1.23-1.30 (m, 1H), 1.42-1.56 (m, 3H), 1.72-1.84 (m, 1H), 1.87-2.04 (m, 3H), 2.17-2.26 (m, 1H), 2.31-2.49 (m, 3H), 2.56-2.67 (m, 1H), 3.00-3.10 (m, 1H), 3.32-3.40 (m, 1H), 3.75 (d, J=2.45 Hz, 2H), 4.67-4.75 (m, 1H); MS (DCl/NH3) m/z 251 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][NH2:14])[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][NH:14][C:21]3[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=3)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CN)O2
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(OC)nc(NCC2COC3(CCC(C(C)(C)C)CC3)O2)n1
Yield: 66 %

Procedure:
8-t-butyl-2-aminomethyl-1,4-dioxaspiro(4,5)decane (3.3 g, 14.5 mmol), 4,6-dimethoxy-2-methylsulfonyl-pyrimidine (3.16 g, 14.5 mmol) and potassium carbonate (2.76 g, 20 mmol) were heated to 160° C. for 1 hour. The reaction mixture was then extracted with toluene and the concentrated extracts purified by flash chromatography using a 3:1 mixture of toluene and ethylacetate. 3.5 g of a faint yellow oil was obtained which crystallised on standing. NMR analysis indicated the product being a mixture of diastereoisomers. M.p.: 76°-106° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccccc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-ethynylbenzene (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.39 (s, 1H), 7.49-7.60 (m, 3H), 7.88-7.97 (m, 2H), 8.17 (ddd, J=9.3, 2.9, 1.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.97 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[N:13]=2)=[CH:5][CH:4]=1.[CH2:21]=O>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[CH2:21][NH:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[C:12]3=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1ccc(-c2nc(-c3ccccc3N)c[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2ncc3n2CNc2ccccc2-3)cc1
Reaction time: 0.03 h

Procedure:
2-(4-Methoxyphenyl)-4-(2-aminophenyl)imidazole (5 g) is dissolved in acetic acid (20 ml) and formaldehyde (37% in water, 1.53 ml) is added. The reaction is stirred for 2 min., diluted with ethyl acetate (100 ml), and extracted with 5%HCl (250 mnl). The aqueous layer is basified with K2CO3, then extracted with ethyl acetate. The organic layer is evaporated under reduced pressure and the residue is recrystallized from dichloromethane to afford 3-(4-methoxyphenyl)-5,6-dihydroimidazo[1,5-c]quinazoline (3 g) as a light brown solid. m.p. 190-191° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:27]([S:34][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=3)[NH:10][C:4]=12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: SCc1ccccc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1SCc1ccccc1
Temperature: 80 °C

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.10 g, 0.25 mmol), benzyl mercaptan (0.036 ml, 0.3 mmol) and potassum tert-butanolate (0.071 g, 0.63 mmol) were dissolved in DMF (1 ml) and heated to 80° C. for 48 h. The reaction mixture was diluted with EtOAc and extracted with 2M HCl. The aqueous phase was basified with 10M NaOH and extracted with EtOAc. The organic phase was dried (Na2SO4) and evaporated in vacuo and the residue was dissolved in CH3CN (3 ml) and purified by HPLC-C18, giving the title product as a bis(trifluoroacetate) (37%).
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:12]=[N:13][C:14]([S:17][CH:18]3[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=1>>[CH:1]1([CH:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH:18]3[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)[C:8]([NH:21][C:22]2[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)/C(=C/C1CCCC1)c1ccc(SC2CC2)nc1
Reactant: CCOC(=O)c1cnc(N)s1
Product: CCOC(=O)c1cnc(NC(=O)C(=CC2CCCC2)c2ccc(SC3CC3)nc2)s1

Procedure:
(E)-3-Cyclopentyl-2-(6-cyclopropylsulfanylpyridin-3-yl)acrylic acid (Preparation 15, 250 mg, 0.86 mmol) was condensed with ethyl 2-aminothiazole-5-carboxylate (297 mg, 1.73 mmol), using the method described in EXAMPLE 12, to furnish ethyl 2-[3-cyclopentyl-2-(6-cyclopropylsulfanylpyridin-3-yl)acryloylamino]thiazole-5-carboxylate: m/z (ES+)=444.3 [M+H]+. This ester was saponified, employing a procedure similar to that described in Step 3 of Preparation 16, to give 2-[3-cyclopentyl-2-(6-cyclopropylsulfanylpyridin-3-yl)acryloylamino]thiazole-5-carboxylic acid: m/z (ES+)=416.1 [M+H]+. Oxidation of this thioether, utilising an approach similar to that described in EXAMPLE 35, afforded 2-[3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)acryloylamino]thiazole-5-carboxylic acid: m/z (ES+)=448.2 [M+H]+. This carboxylic acid (52 mg, 116 μmol) was condensed with MeNH2.HCl in the presence of NEt3, utilising the general procedure described in EXAMPLE 12, to give the title compound: RTA=3.29 min; m/z (ES+)=461.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])C)=[N:4][C:3]=1[CH3:10].[O:11]1CC[CH2:13][CH:12]1C=O>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:9][CH2:13][CH2:12][O:11]2)=[N:4][C:3]=1[CH3:10]
Reactant: O=CC1CCCO1
Reactant: Cc1nc(C(C)C)[nH]c1I
Product: Cc1nc(C2CCCO2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 159.2, except tetrahydrofuran-2-carbaldehyde was used in place of isobutyraldehyde. m/z (ES+) 279 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10]C)=O.[NH3:12]>CO>[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([NH2:12])=[O:10]
Reactant: N
Reactant: COC(=O)C1COCCN1
Agent: Cl
Solvent: CO
Product: NC(=O)C1COCCN1
Yield: 99 %

Procedure:
A mixture of methyl morpholine-3-carboxylate hydrochloride (0.55 g, 3.0 mmol) and a solution of NH3 in methanol (7 mol/L, 20 mL) was stirred at 50° C. for 24 hours in a sealed tube. The mixture was concentrated in vacuo to give the title compound as glutinous semisolid (0.39 g, 99%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)[CH:9]1[CH2:14][CH2:13][O:12][C:10]1=[O:11].[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.O>[C:22]([O:7][CH:8]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)[CH:9]1[CH2:14][CH2:13][O:12][C:10]1=[O:11])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OCCC1C(O)C1CC2C=CC1C2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC(C1CCOC1=O)C1CC2C=CC1C2
Reaction time: 10 h
Yield: 98 %

Procedure:
To 127 g of pyridine were added 208 g of α-[hydroxy(5-norbornen-2-yl)methyl]-γ-butyrolactone (Monomer 1), 123 g of acetic anhydride and 6 g of 4-dimethylaminopyridine. Reaction was effected at 25° C. for 10 hours. Water, 30 g, was added to the reaction mixture to stop reaction, followed by hexane extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. Purification by silica gel column chromatography yielded 245 g (yield 98%) of α-[acetoxy(5-norbornen-2-yl)methyl]-γ-butyrolactone.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([CH:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]2)=[O:7])[CH2:3]1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1.[H-].[Na+]>CS(C)=O.CCOC(C)=O>[CH3:32][C:28]1[N:29]=[CH:30][C:31]([O:1][CH:2]2[CH2:3][N:4]([C:6]([CH:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:10][CH2:9]3)=[O:7])[CH2:5]2)=[CH:26][CH:27]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: O=C(OCc1ccccc1)N1CCCC(C(=O)N2CC(O)C2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OC2CN(C(=O)C3CCCN(C(=O)OCc4ccccc4)CC3)C2)cn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
To a solution of benzyl 4-[(3-hydroxyazetidin-1-yl)carbonyl]azepane-1-carboxylate (97 mg, 0.29 mmol) and 4-chloro-2-methylpyridine (52 μl, 0.46 mmol) in DMSO (2 ml) was added NaH (37 mg of a 60% dispersion in mineral oil, 0.93 mmol). The mixture was stirred at room temperature for 12 hours, 50° C. for 3 hours and a further 12 hours at room temperature. The reaction was then diluted with EtOAc (20 ml) and washed with water (3×10 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 99:1:1 to 95:5:1 DCM/MeOH/2M NH3 in MeOH) to give the title product as colourless oil (35 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]3[NH:1][C:2]4=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]5[C@@H:15]6[CH2:16][C@@H:12]([CH:13]=[CH:14]6)[C@@H:11]5[C:17]([NH2:19])=[O:18])=[C:7]4[N:8]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Product: CN1CCN(c2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)ccnc4[nH]3)cc2)CC1
Yield: 18.7 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-(4-methyl-piperazin-1-yl)-benzaldehyde (43.3 mg, 0.212 mmol) were reacted to produce 16 mg (19%) of the title compound. mp: 220-222° C., 1H NMR (300 MHz, DMSO-d6): 12.81 (s, 1H), 7.98 (d, J=8 Hz, 2H), 7.85 (d, J=5 Hz, 1H), 7.66 (s, 1H), 7.16 (s, 1H), 7.04 (d, J=8 Hz, 2H), 6.75 (m, 1H), 6.37 (d, J=8 Hz, 1H), 6.33 (s, 2H), 3.88 (br s, 1H), 3.32 (s, 6H), 2.88 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.45 (br s, 4H), 1.42 (d, J=8 Hz, 1H). MS: 444 (M+H), HPLC: 1.57 min (G method).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH2:5][CH2:6][C:7]2=[O:15].O1CCOCC1>[Pd].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]2[C:8]=1[C:7](=[O:15])[CH2:6][CH2:5][CH:4]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)c2c(F)ccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1ccc(F)c2c1C(=O)CCC2N1C(=O)c2ccccc2C1=O

Procedure:
To 320 mg of the compound prepared in (9) above were added 9 ml of dioxane and 15 ml of ethanol. The mixture was catalytically hydrogenated with 290 mg of 10% palladium-on-carbon. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 206 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH:41]([NH2:43])[CH3:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:43][CH:41]([CH3:42])[CH2:40][O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: COCC(C)N
Product: COCC(C)Nc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methoxy-1-methylethylamine according to conditions described in general procedure C. Mp: 94-95° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.97 (s, 3 H), 1.56-1.61 (m, 6 H), 3.00-3.32 (m, 9H), 4.10 (s, 1 H), 6.31 (s, 1 H), 6.95-7.03 (m, 2 H), 7.15 (d, J=9.1 Hz, 1 H), 7.38 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.50-7.62 (m, 3 H), 7.79-7.82 (m, 1 H), 7.95-7.97 (m, 1 H), 8.20 (s 1 H), 10.40 (s, 1 H).