Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:28][N:25]1[CH2:24][CH2:23][CH:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[S:57])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (153 mg) and (+)-10-camphorsulfonic acid (162 mg) in ethanol (4.0 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.93 ml) at room temperature, followed by stirring for 3 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (71.8 mg, 33%) as white powder.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH2:27]>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:27][CH2:26][C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Reactant: NCc1cccs1
Solvent: CCO
Product: O[C@H](CNCc1cccs1)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 2-thiophenemethylamine and ethanol essentially as described above in Example 94. Purity by LC/MS=99%, [M+H]+=396.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.Cl.[CH3:30][O:31][C:32]([CH:34]1[NH:39][CH2:38][C:37]2[N:40]([CH2:43][C:44](=[O:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:41]=[N:42][C:36]=2[CH2:35]1)=[O:33].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:30][O:31][C:32]([CH:34]1[N:39]([C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:38][C:37]2[N:40]([CH2:43][C:44](=[O:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:41][NH:42][C:36]=2[CH2:35]1)=[O:33]
Reactant: COC(=O)C1Cc2ncn(CC(=O)c3ccccc3)c2CN1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 9.3 g dicyclohexycarbodiimide, 6.1 g hydroxybenzotriazole hydrate, 9.5 g diphenylacetic acid and 100 mL acetonitrile is stirred at 25° C. for 15 min (suspension A). A mixture of 15.8 g methyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-3H-imidazo-[4,5-c]pyridine-6-carboxylate dihydrochloride, 14.8 mL diisopropylethylamine and 100 mL acetonitrile is stirred 10 min at 25° C. then treated with suspension A, using 100 mL acetonitrile to complete the transfer. The resulting suspension is stirred 48 hr, filtered and the filtrate is evaporated, dissolved in dichloromethane, washed with 10% Na2CO3, dried and evaporated. Chromatography on silica gel (chloroform-methanol, 99:1) gives methyl-5-diphenylacetyl-3-(2-oxo-2-phenyl-ethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate as foam. MS (FAB) 494 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[CH:20]=[C:19]([NH2:21])[C:18]([F:22])=[CH:17][C:16]=3[F:23])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([F:23])=[CH:17][C:18]([F:22])=[C:19]([NH:21][C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N)cc21
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A solution of 7-amino-3-(5-amino-2,4-difluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (500 mg, 1.58 mmol) and TEA (638 mg, 6.32 mmol) in DCM (5 mL) was treated drop-wise with phenyl isocyanate (503 mg, 4.8 mmol) and stirred at RT overnight. The mixture was concentrated to dryness and purified by silica gel chromatography (EtOAc/pet ether) to afford 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (500 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.13 (m, 1H), 7.83 (s, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.39-7.34 (m, 1H), 7.29-7.25 (m, 2H), 6.99-6.95 (m, 1H), 6.58 (s, 2H), 6.34 (s, 1H), 4.13-4.08 (q, J=0.8 Hz, 2H), 1.22 (t, J=6.8 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH:10]=O)=[CH:3][CH:2]=1.[CH:12]12[N:18]([C:19](=[O:51])[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=3)=[C:26]4[CH2:40][CH2:41][NH:42][CH2:43][CH2:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)([CH3:22])[CH3:21])[CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:15]12[N:18]([C:19](=[O:51])[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([C:32]3[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=3)=[C:26]4[CH2:40][CH2:41][N:42]([CH2:10][CH2:9][CH2:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:43][CH2:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)([CH3:21])[CH3:22])[CH:12]([CH2:13][CH2:14]1)[CH2:17][CH2:16]2
Reactant: O=CCCCc1ccncc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNCCc2cccnc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN(CCCCc2ccncc2)CCc2cccnc2)c1
Reaction time: 17.5 h
Yield: 75.6 %

Procedure:
To a solution of 4-(pyridin-4-yl)butyraldehyde (29 mg in 1.5 mL dry methanol) was added 18 mg of 1-(7-aza-bicyclo[2.2.1]hept-7-yl)-2-(2-(3,5-dimethylphenyl)-3-[2-(2-pyridin-3-yl-ethylamino)-ethyl]-1H-indol-5-yl}-2-methylpropan-1-one followed by 10 mg 3A powdered molecular seives. To this mixture, 13 mg sodium cyanoborohydride was added and the pH adjusted to 5.5 by the addition of 10% methanolic acetic acid. After 17.5 hours, the reaction was quenched by the addition of saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic portion was washed successively with saturated ammonium chloride, sodium bicarbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 90:10) gave the title compound (17 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7](=[O:17])[CH:6]=[CH:5]2.[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]=[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[N:8]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cn1c(=O)ccc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(=O)ccc2cc(C#C[Si](C)(C)C)ccc21
Temperature: 80 °C

Procedure:
Methyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.67 mmol), CuI (0.67 mmol) and PdCl2(PPh3)2 (0.40 mmol) were dissolved in triethylamine (3 mL) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 5 minutes. Ethynyltrimethylsilane (3.5 mmol) was added to the reaction mixture and the tube was sealed and placed into an oil bath pre-heated to 80° C. for 8 h. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min)=2.759, method [1], MS (ESI) 314.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH2:9])=[O:8].C([N-]C(C)C)(C)C.[Li+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:19](=[O:20])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:8]
Reactant: NC(=O)c1ccccn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC(=O)c1ccccn1)Oc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 16.9 %

Procedure:
Picolinamide (0.500 g, 16 mmol) was dissolved in THF (25 mL) and cooled to −10° C. To the solution, lithium diisopropyl amide (5.1 mL, 2.0 M in heptane/THF/ethyl benzene, 10 mmol) was added dropwise. The resulting mixture was stirred at −10° C. for 15 minutes then treated with phenyl chloroformate (1.69 mL, 12.3 mmol) in THF (5 mL). After 20 minutes the reaction was warmed to room temperature and stirred for 3 hours at which time the reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with EtOAc and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20-50% EtOAc in heptane) to provide the desired product (0.504 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.18-7.26 (m, 3H) 7.34-7.41 (m, 2H) 7.54 (ddd, J=7.63, 4.78, 1.23 Hz, 1H) 7.92 (td, J=7.74, 1.70 Hz, 1H) 8.28 (dt, J=7.82, 1.09 Hz, 1H) 8.62 (ddd, J=4.77, 1.67, 0.93 Hz, 1H) 10.47 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH:17][NH2:18])=[O:16])[CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.Cl>ClCCl>[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH:17][NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)=[O:16])[CH2:10]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
A mixture of 1-(4-fluoro-benzoyl)-(S)-piperidine-3-carboxylic acid hydrazide hydrochloride, already prepared as described in Example 57 (C) (2.97 g, 11.2 mmol), 4-fluorobenzoic acid (1.68 g, 11.2 mmol), HOBT (1.5 g, 11.2 mmol), EDCI.HCl (3.2 g, 16.8 mmol) and dry triethylamine (5.43 mL, 39.5 mmol) in dry dichloromethane (80 mL) was kept under stirring overnight at ambient temperature, under nitrogen atmosphere. HCl 1N (80 mL) was then added and the phases separated. The organic layer was washed with HCl 1N (80 mL), with NaOH 1N (80 mL×2 times), then with water (80 mL). Evaporation of the organic solvent afforded a crude oil which was purified by flash chromatography (silica gel, eluent: DCM/MeOH/NH4OH 98/2/0.2). The compound obtained after column chromatography was purified again by flash chromatography (silica gel, eluent: DCM/MeOH/NH4OH 98/2/0.2) to provide the pure 4-fluoro-benzoic acid N′-[(S)-1-(4-fluoro-benzoyl)-piperidine-3-carbonyl]-hydrazide as a white solid (250 mg).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][O:18][C:17]2=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:23]>O1CCCC1.CO>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:22])[O:18][CH2:19][C:20]([NH2:23])=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1COC(=O)N1CCCCOc1cccc2ccccc12
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)COC(=O)NCCCCOc1cccc2ccccc12
Yield: 46.2 %

Procedure:
1.50 g (5.0 mmol) of 3-[4-(1-naphthalenyl-oxy)butyl]-1,3-oxazolidine-2,4-dione, prepared in Step 3.1., are dissolved in a mixture of 10 ml of tetrahydrofuran and 28 ml of a 7N solution of ammonia (200 mmol) in methanol. The solution is left to react overnight at ambient temperature and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol. It is recrystallized from ethyl acetate and then washed with diethyl ether, to give 0.73 g of product in white solid form.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6](=O)[C:5]2=O)[CH2:3][CH2:2]1.B.O1CCCC1>O1CCCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ccccc2n(C2CC2)c1=O
Agent: B
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCN2C1CC1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
To a stirred suspension of 1-cyclopropyl-1,4-dihydro-quinoxaline-2,3-dione (10.0 g, 49.45 mmol, 1.0 equiv) in tetrahydrofuran (500 mL) was added dropwise a 1 M solution of borane-tetrahydrofuran complex (108.8 mL, 108.8 mmol, 2.2 equiv; [CAS RN 14044-65-6]) and the reaction mixture stirred at room temperature over night. The solvent was removed by evaporation under reduced pressure and the crude reaction mixture extracted from a saturated aqueous solution of sodium bicarbonate (100 mL) with ethyl acetate (three times 100 mL). The combined organic phases were dried over sodium sulfate and purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate to give 4.2 g (49%) of the title compound as a light yellow solid. MS (ISP): m/z=175.4 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.B(F)(F)F.CC[O:29]CC.[OH-].[K+].OO.B(O)(O)O>C(COC)OC.O>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)[CH:14]([OH:29])[CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Brc1cccc(C2=CCN(Cc3ccccc3)CC2)c1
Reactant: CCOCC
Agent: FB(F)F
Agent: OB(O)O
Agent: OO
Solvent: COCCOC
Solvent: O
Product: OC1CN(Cc2ccccc2)CCC1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3.15 g (83.3 mmol) of sodium borohydride were added portionwise at room temperature to a suspension of 9.5 g (28.9 mmol) of 1-benzyl-4-(3-bromophenyl)-1,2,3,6-tetrahydro-pyridine in 65 ml of absolute dimethoxyethane (DME). Thereafter, a solution of 17.7 ml (20.0 g 140.9 mmol) of boron trifluoride etherate in 11 ml of DME was added dropwise at 15-200° C. and the mixture was stirred at room temperature for 2 hours. Subsequently, a solution of 18.3 g (326 mmol) of potassium hydroxide in 100 ml of water was added dropwise within 30 minutes at 20-25° C. Finally, 55 ml of 30% hydrogen peroxide solution were added dropwise within 30 minutes at 20-25° C. The mixture was stirred at room temperature for 30 minutes and heated to reflux for 3 hours. After cooling the reaction mixture the separated boric acid was filtered off. Subsequently, the filtrate was partitioned between methylene chloride and water, the organic phase was dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of ethyl acetate and methylene chloride as the eluent. There were obtained 6.3 g (63% of theory) of (3RS,4RS)-1-benzyl-4-(3-bromophenyl)-piperidin-3-ol as a colourless oil. MS: 345, 347 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[C:11]2=[S:30])[CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:33])=O>>[Cl:33][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[C:11]2=[S:30])=[CH:3][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CO)c(F)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
The title compound was prepared according to General Method 10. 4-[3-(3-Fluoro-4-hydroxymethyl-phenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile (0.5 g, 1.14 mmol) was dissolved in thionyl chloride (5 mL) and the solution was stirred at 100° C. for 12 h. The reaction mixture was concentrated under reduced pressure to obtain 300 mg of product.
Reaction SMILES: [Si]([O:8][C:9]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([N+:23]([O-:25])=[O:24])=[C:20]([C:26]([NH2:28])=[O:27])[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])(C(C)(C)C)(C)C.CC(O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:8][C:9]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([N+:23]([O-:25])=[O:24])=[C:20]([C:26]([NH2:28])=[O:27])[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[6-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)pyridin-3-yl]-2-nitrothiophene-3-carboxamide (665 mg, 1.58 mmol) in THF (10 mL) were added AcOH (0.36 ml, 6.13 mmol) and TBAF (1.0 M in THF, 6.31 mL, 6.31 mmol). The sealed reaction was stirred at 90° C. for 18 h. Additional AcOH (0.361 ml, 6.13 mmol) and TBAF (6.31 mL, 6.31 mmol) were added, and the reaction was stirred at 90° C. for another 24 h. The brown solution was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were washed with brine (2×), dried (MgSO4), filtered, and evaporated. Flash chromatography of the crude residue (50-100% EtOAc/hexanes) provided a yellow residue that was triturated with Et2O and filtered to isolate the title compound as a yellow solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1>>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:30]=[C:28]([NH:27][C:23]3[CH:22]=[C:21]([OH:20])[CH:26]=[CH:25][CH:24]=3)[N:29]=2)=[CH:8]1)[CH3:17]
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Reactant: N=C(N)Nc1cccc(O)c1
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc(O)c3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one and 1-(3-hydroxyphenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 1.18 (t, 3H, J=7.2 Hz, CH3), 4.37 (q, 2H, J=7.2 Hz, CH2), 6.40 (m, 1H, Ph-H), 7.08 (t, 1H, J=7.6 Hz, Ph-H), 7.18 (m, 1H, Ar—H), 7.24 (d, 1H, J=5.6 Hz, Pyrimidin-H), 7.37 (s, 1H, Ph-H), 8.36 (m, 2H, Pyrimidin-H and Ar—H), 8.59 (s, 1H, Ar—H), 9.00 (d, 1H, J=8.0 Hz, Ph-H), 9.24 (s, 1H, Ar—H), 9.33 (s, 1H, NH). MS (ESI+) m/z 332.1355 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[N:14]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1>[Pd].C(OCC)(=O)C.CN(C=O)C.CO.C(O)(=O)C>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[N:14]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reaction time: 0.67 h
Yield: 80.4 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7 g, 17.7 mmol) and 10% palladium-on-charcoal catalyst (700 mg) in ethyl acetate (250 mL), DMF (50 mL), methanol (50 mL) and acetic acid (0.7 mL) was stirred under hydrogen at atmospheric pressure for 40 minutes. The catalyst was removed by filtration and the solvent removed from the filtrate by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (4.36 g, 80%).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10](Br)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ncccc2c(Br)cn1Cc1ccccc1
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2ncccc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
A mixture of 7-benzyl-5-bromo-1,7-naphthyridin-8(7H)-one (0.574 g, 1.82 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.385 g, 2.73 mmol) and Na2CO3 (0.579 g, 5.46 mmol) was degassed under nitrogen. Then toluene (30 mL), ethanol (30 mL) and water (3 mL) were added. The reaction mixture was degassed again and Pd(PPh3)4 (0.210 g, 0.12 mmol) was added and degassing procedure was repeated. The reaction was stirred at 90° C. for 6 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water then brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 97:3 dichloromethane/methanol) to give 7-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one (0.341 g, 56%) as a tan solid: mp 168-170° C.; 1H NMR (400 MHz, CDCl3): δ 8.92-9.00 (m, 1H), 7.52-7.60 (m, 2H), 7.29-7.42 (m, 5H), 7.04 (s, 1H), 5.26-5.43 (m, 2H), 2.22 (s, 3H), 2.04 (s, 3H); ESI MS m/z 332.0 [M+H]+.
Reaction SMILES: [CH2:1]([Cl:5])[C:2](=C)[CH3:3].[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC=CCCl>>[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:1]([Cl:5])[CH:2]=[CH2:3]
Reactant: C=C(C)CCl
Agent: CC=CCCl
Solvent: C=Cc1ccccc1
Product: C=CCCl
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
About 1 part by weight of a fine granular hydrated silica, 3 parts by weight of methallyl chloride and 0.5 part by weight of styrene are mixed then heated to the boiling temperature of methyallyl chloride while agitating at ambient temperature and pressure for 1 to 12 hours, thereby producing a soft, light yellow, solid poly (allyl chloride styrene) copolymer.