Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CC#N>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: C1COCCN1
Reactant: Cc1nc(NC(=O)CCCl)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Solvent: CC#N
Product: Cc1nc(NC(=O)CCN2CCOCC2)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1

Procedure:
By treatment of 3-chloro-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with morpholine. Anal. RP-HPLC: tR=12.7 min (10-70% MeCN, purity >95%). 1H-NMR (CDCl3) δ: 1.50 (m, 2H, CH2), 2.52 (s, 3H, CH3), 3.05-3.78 (m, 8H, CH2), 3.81 (m, 2H, CH2), 7.12 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.30 (d, 2H, J=7.0 Hz, Ph-H), 7.80 (d, 2H, J=7.0 Hz, Ph-H), 8.51 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.80 (brs, 1H, NH).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][N:25]([C:28]3[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=3)[CH2:24][CH2:23]2)[O:19]1>CN(C)C=O>[N:1]1([CH2:17][CH:18]2[CH2:22][O:21][C:20]3([CH2:23][CH2:24][N:25]([C:28]4[N:29]=[C:30]([O:36][CH3:37])[CH:31]=[C:32]([O:34][CH3:35])[N:33]=4)[CH2:26][CH2:27]3)[O:19]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COc1cc(OC)nc(N2CCC3(CC2)OCC(CCl)O3)n1
Reactant: c1ccc2[nH]nnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(N2CCC3(CC2)OCC(Cn2nnc4ccccc42)O3)n1
Temperature: 120 °C

Procedure:
To 37.63 gm (0.3163 mole) of benzotriazole and 35 gm of potassium carbonate in Dimethylformamide (DMF) (350 ml) was added slowly under stirring 82 gm of 2-chloromethyl-8-(4,6-dimethoxy-pyrimidin-2-yl)-1,4-dioxa-8-azaspiro[4,5]decane (intermediate for compound 7) in DMF (300 ml). After the addition, reaction mixture was heated to 120° C. and maintained for 30 hrs. The reaction mixture was cooled to room temperature 28° C. and filtered. The solvent was distilled off to get the product. It was a thick dark brown liquid. Yield of product was 90%
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([I:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.C[O-].[Na+].CO.CN([CH:33]=[O:34])C.C(OCC)(=O)C>CCCCCC>[I:11][C:9]1[CH:10]=[C:2]([O:34][CH3:33])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(I)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A mixture of 5-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.226 g, 0.5 mmol), 30% sodium methoxide-methanol (0.7 mL) and DMF (0.12 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.071 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.83 (s, 3H), 4.12 (s, 2H), 4.75 (s, 2H), 6.87 (bs, 1H), 7.17 (d, 2H), 7.33 (d, 2H), 7.44 (bs, 1H). GC-MS: m/z 463 (M)+, 394 (M−69)+, 378 (M−85)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.C(=O)([O-])[O-].[K+].[K+].[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[N:16]1([C:22]([N:2]2[CH2:3][CH:4]3[CH2:8][C:7](=[O:9])[CH2:6][CH:5]3[CH2:1]2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C1CC2CNCC2C1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC2CN(C(=O)N3CCOCC3)CC2C1
Yield: 100 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (574 mg, 2.4 mmol) was dissolved in 20 mL of acetonitrile with stirring, and potassium carbonate (0.397 g, 2.88 mmol) was then added to the solution in an ice-water bath, followed by morpholine-4-carbonyl chloride (0.323 mL, 2.64 mmol). Upon completion of the addition, the reaction mixture was stirred overnight in an ice-water bath, then the solvent was evaporated, and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(morpholine-4-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 7a (0.572 g, yield 77.3%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.CC(C)([O-])C.[K+].[O:15]1[CH:19]=[CH:18][C:17]2[CH:20]=[C:21]([CH:24]3[CH2:26][O:25]3)[CH:22]=[CH:23][C:16]1=2.Cl>C(OCC)(=O)C.CS(C)=O>[O:15]1[CH:19]=[CH:18][C:17]2[CH:20]=[C:21]([CH:24]([OH:25])[CH2:26][O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:22]=[CH:23][C:16]1=2
Reactant: c1cc2cc(C3CO3)ccc2o1
Reactant: OCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OC(COCc1cccnc1)c1ccc2occc2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 14.2 %

Procedure:
A mixture of 1.6 g of 3-pyridinemethanol, 1.7 g of potassium tert-butoxide and 23 ml of dimethyl sulfoxide was heated to 80° C. Thereto was added 2.4 g of 2-(benzo[b]furan-5-yl)oxirane. The resulting mixture was stirred at 85°-90° C. for 15 minutes. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The resulting mixture was adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer was separated and 30 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 9.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant:chloroform/ethanol=50/1) to obtain 0.56 g of 1-(benzo[b]furan-5-yl)-2-(pyridin-3-ylmethoxy)ethanol (compound No. 339).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:9])[CH3:16])=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (4-bromophenyl)phenyl methanone (0.750 g, 2.87 mmol) in anhydrous THF (25.00 mL) was added solution of methylmagnesium bromide in THF (3.00 M, 1.91 mL) via a syringe at −78° C. The resulting mixture was stirred for 2 hours at −78° C. The reaction was quenched with 10 mL of a saturated aqueous NH4Cl solution at −78° C. and allowed to warm to rt. The product was extracted with EtOAc (2×) and brine (2×). The aqueous layer was back-extracted with DCM several times. The organic layers were combined, dried, filtered and concentrated in vacuo to give the product which was used for next step without any further purification. 1H NMR (400 MHz, CDCl3): δ 1.90 (3H, s) 7.19-7.33 (5H, m) 7.33-7.43 (4H, m).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:22][CH2:23][N:24]([CH2:37][CH:38]4[CH2:40][CH2:39]4)[CH2:25][CH2:26]3)[C@H:17]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:16]2)=[O:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: BrCC1CC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccc(F)cc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(CC3CC3)CC2)[C@H](c2ccc(F)cc2)C1

Procedure:
The title compound, MS: m/e=558.3 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-piperazin-1-yl-piperidin-1-yl]-methanone and bromomethyl cyclopropane.
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].Cl[CH2:8][C:9]1[O:13][N:12]=[C:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=2)[N:10]=1.[OH:22][C:23]1[C:28]([CH3:29])=[C:27]([OH:30])[CH:26]=[CH:25][C:24]=1[C:31](=[O:33])[CH3:32].C1C2C(C3ON=C(N)N=3)CN(C2)C1>CN(C)C=O.O>[OH:22][C:23]1[C:28]([CH3:29])=[C:27]([O:30][CH2:8][C:9]2[O:13][N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=3)[N:10]=2)[CH:26]=[CH:25][C:24]=1[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)c1ccc(O)c(C)c1O
Reactant: ClCc1nc(Cc2cccc(I)c2)no1
Agent: Nc1noc(C2CN3CCC2C3)n1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(C)c1O
Temperature: 60 °C
Yield: 53.8 %

Procedure:
Add lithium carbonate (49 mg, 0.66 mmol) and 5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole (200 mg, 0.60 mmol) to a solution of 1-(2,4-dihydroxy-3-methyl-phenyl)-ethanone (110 mg, 0.66 mmol) in anhydrous dimethylformamide (20 mL) 4]oxadiazole (200 mg, 0.60 mmol). Heat the reaction mixture at 60° C. overnight. Cool the reaction mixture to RT, pour into H2O, and extract with diethyl ether (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the title compound (150 mg). LC-MS (m/e): 463 (M−1).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]#[N:24].[N:25]([Si](C)(C)C)=[N+:26]=[N-:27].C([Sn](=O)CCCC)CCC.CN(C)C=O>C(OCC)(=O)C.C(OCC)C>[N:24]1[NH:25][N:26]=[N:27][C:23]=1[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][CH:13]=3)=[CH:6][CH:5]=2)[CH2:10][CH2:11][C:2]1=[O:1]
Reactant: N#CCN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1Cc1nn[nH]n1
Temperature: 160 °C
Yield: 80 %

Procedure:
A Biotage microwave vial was charged with 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetonitrile (66 mg, 0.20 mmol), azidotrimethylsilane (46 mg, 0.40 mmol), dibutyltin oxide (8 mg, 0.03 mmol), and anhydrous N,N-dimethylformamide (2.5 mL), and the vial capped. The reaction mixture was heated to 160° C. and irradiated for 25 minutes. LCMS showed only ca 63% conversion. Additional azidotrimethylsilane (46 mg, 0.40 mmol) was added, and heated again at 160° C. for an additional 30 minutes. LCMS showed the disappearance of starting material. The reaction mixture was diluted with ethyl acetate (30 mL), washed with 30% aqeuous ammonium chloride (2×10 mL), brine (20 mL), and dried over sodium sulfate. The solvent was removed from the solution under reduced pressure to give a pale yellow solid. Ethyl ether (3 mL) was added, sonicated, filtered, washed with ethyl ether (10 mL), dried to afford 1-((2H-tetrazol-5-yl)methyl)-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one as a white solid (59 mg, 0.16 mmol, 80%). LCMS mz 374.0 (M+H), anal HPLC >97% purity, 1HNMR (400 MHz, CD3CN) δ 7.83 (m, 4H); 7.65 (d, J=2.0 Hz, 1H); 7.62 (dd, J=8.4 and 2.1 Hz, 1H); 7.30 (d, J=8.6 Hz, 1H); 5.46 (s, 2H); 3.11 (m, 2H); 2.77 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[F:38])[NH2:34].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)C.[Cl-].[Na+].O.C(O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:34][C:33]1[CH:35]=[CH:36][C:37]([F:38])=[C:31]([Cl:30])[CH:32]=1
Reactant: O=c1[nH]cnc2cc([N+](=O)[O-])c(Br)cc12
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1Br
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Formamidine acetate (4.51 g, 43.3 mmol) and methoxyethanol (60 mL) were added to 5-bromo-4-nitroanthranyl acid (described in JP-A-2000-169451) (5.65 g, 21.7 mmol) and the mixture was refluxed for 4 hrs. Water was added until the reaction mixture becomes about 200 mL and the precipitate was filtered and washed with water. The precipitate was dried under reduced pressure to give 6-bromo-7-nitro-3H-quinazolin-4-one (5.21 g, 64%). To a solution (20 mL) of 6-bromo-7-nitro-3H-quinazolin-4-one (1.34 g, 5.0 mmol) in toluene were added phosphorous oxychloride (0.70 mL, 7.5 mmol) and diisopropylethylamine (1.29 mL, 7.5 mmol), and the mixture was stirred at 80° C. for 5 hrs. A solution (5 mL) of 3-chloro-4-fluoroaniline (1.09 g, 7.5 mmol) in isopropanol was added at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into hexane (30 mL) and the mixture was stirred at room temperature for 30 min. The product was collected by filtration and dried. To this compound were added reduced iron (1.10 g, 20.0 mmol), 1N hydrochloric acid (10 mL) and ethanol (30 mL) and the mixture was refluxed for 1 hr. 1N Aqueous sodium hydroxide solution (10 mL) was added and the mixture was stirred at 50° C. for 30 min. Saturated brine was added and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was suspension-washed with acetonitrile (10 mL) to give 6-bromo-N4-(3-chloro-4-fluorophenyl)-4,7-quinazolinediamine (5′) (987 mg, 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:37])[C@@H:15]([NH2:36])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:37])[C@@H:15]([NH:36][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N

Procedure:
(S)-2-(2-amino-5-chloro-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester was prepared following Procedure A using 2-amino-5-chloro-benzoic acid (1.23 g, 7 mmol), (S)-2-amino-3-(4′-phenoxy-biphenyl-4-yl)propionic acid methyl ester (2.43 g, 7 mmol), HBTU (3.19 g, 8.4 mmol) and DIEA (2.46 mL, 14 mmol) in DMF (35 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:3, 1:2) gave the title compound as yellow solid (3.25 g, 6.49 mmol,).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:32][C@@H:31]([CH3:33])[NH:30][CH2:29][C@@H:28]2[CH3:34])=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([N:30]1[CH2:29][C@H:28]([CH3:34])[N:27]([CH2:26][C:25]2[CH:35]=[CH:36][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:32][C@H:31]1[CH3:33])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)/C=C/c1ccc(Cl)cc1NC(=O)OC(C)(C)C
Yield: 82.7 %

Procedure:
(E)-3-(2-tert-Butoxycarbonylamino-4-chlorophenyl)-acrylic acid (595 mg, 2.0 mmol) and (2S,5R)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (Mavunkel, Babu J. et al., WO 00/71535) (445 mg, 2.0 mmol) were dissolved in CH2Cl2, combined with EDCl.HCl (384 mg, 2.0 mmol) and stirred for 3 hours at room temperature. The reaction mixture was purified via chromatography (SiO2, EtOAc/hexanes 2/8) to yield the title compound as colorless foam (830 mg, 81%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][CH2:12][CH2:13]C)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N)C>>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCCNC1CCC2(CC1)OCCO2
Agent: CCN
Product: CCNC1CCC2(CC1)OCCO2

Procedure:
(1,4-Dioxa-spiro[4.5]dec-8-yl)-ethylamine (4A) is prepared operating as described for 1A with 7.85 mL (120 mmol) of cooled liquid ethylamine.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH:11]=[CH:12][CH2:13][N+:14]1[CH:18]=[CH:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=1>C(O)C.[Pd]>[Cl-:2].[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][N+:14]1[CH:18]=[CH:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=1
Reactant: CCCCCCCn1cc[n+](CC=CCc2cccc(Cl)c2Cl)c1
Agent: [Pd]
Agent: [Cl-]
Solvent: CCO
Product: CCCCCCCn1cc[n+](CCCCc2cccc(Cl)c2Cl)c1
Reaction time: 2 h

Procedure:
A solution of 17 g (0.042 mole) 1-[4-(2,3-dichlorophenyl)-2-butenyl]-3-heptylimidazolium chloride in 250 ml absolute ethanol and 1.5 g 10% Pd/C catalyst are placed in a small Parr bottle, and hydrogenated at 25 psi for ca. 2 hours. Additional H2 is added as needed to maintain 25 psi pressure. The reaction mixture is filtered and the solvent is evaporated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23]O)[N:21]=1)=[CH:5]2.[CH3:25][NH:26][CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:26]([CH3:27])[CH3:25])[N:21]=1)=[CH:5]2
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CNC
Product: CN(C)CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1

Procedure:
2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 5 and dimethylamine were reacted according to the same procedure as Example 156 to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:29]=1)#[N:2].[SH2:30]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:29]=1)(=[S:30])[NH2:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)ccc3o2)cc1
Reaction time: 18 h

Procedure:
t-Butyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate (430 mg, 1.10 mmol) was dissolved in a mixed solution of pyridine (30 ml) and triethylamine (7 ml), and hydrogen sulfide gas was blown in for 10 minutes at room temperature, which was followed by stirring for 18 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with a 2N aqueous potassium hydrogensulfate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give t-butyl 4-[(5-thiocarbamoyl-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. The solid was dissolved in acetone (50 ml) and methyl iodide (2 ml) was added. The mixture was refluxed under heating for 40 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give t-butyl 4-[[5-[(1-methylthio)iminomethyl]-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. Thereto were added methanol (30 ml) and ammonium acetate (280 mg, 3.64 mmol), and the mixture was refluxed under heating for 3 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/3-3/1) to give 596 mg of hydriodide of compound (8) as a yellow solid (quantitatively in 3 steps).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([N:33]([CH3:35])[CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)cc1
Yield: 13 %

Procedure:
Reaction of 2-(4-methylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 15 (13% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.41 (s, 3H), 2.67 and 3.18 (2d, 6H), 2.84 and 3.08 (2t, 2H), 3.59 and 4.21 (2t, 2H), 4.49 and 5.09 (2s, 2H), 6.33 and 6.82 (2d, 1H), 6.96 and 7.15 (2d, 1H), 7.33-7.37 (m, 2H), 7.55-8.15 (m, 5H), 8.51-8.56 (m, 2H); MS (ESI) m/z 439 ([M+H]+).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:8].O1CCCC1.CN(C=O)C>CO>[N:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH2:4][CH2:5][NH:6][C:7]2=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(NCCCl)Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1NCCN1c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
Sodium hydride (60% in oil, 2.4 g, 60 mmol) was added to a mixture of N-(2-chloroethyl)-N′-(4-pyridyl)urea (11.1 g, 55 mmol), tetrahydrofuran (40 ml) and DMF (40 ml) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with methanol. The solvent was evaporated, and the residue was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (2.4 g, 27%) as white crystals.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:18](=[O:19])[N:17]([CH2:20][CH:21]=[CH2:22])[C:11]2=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=[C:10]2[C:9]=1[OH:23])=[O:7])(C)(C)C.Cl(O)(=O)(=O)=O>C(#N)C>[CH2:20]([N:17]1[C:11]2=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=[C:10]2[C:9]([OH:23])=[C:8]([C:6]([OH:7])=[O:5])[C:18]1=[O:19])[CH:21]=[CH2:22]
Reactant: C=CCn1c(=O)c(C(=O)OC(C)(C)C)c(O)c2ccc(C)nc21
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Product: C=CCn1c(=O)c(C(=O)O)c(O)c2ccc(C)nc21

Procedure:
A solution of 2.0 grams of 1-allyl-7-methyl-4-hydroxypyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acid t-butyl ester in 25 ml. of acetonitrile is treated with 0.7 ml. of 60% aqueous perchloric acid at 0° C. The resulting precipitate is filtered off and washed with ether to obtain 1-allyl-7-methyl-4-hydroxypyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acid.