Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH2:15].C(O)(=O)C>C(O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=Cc1ccncc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2)CC1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
1-Boc-piperazine (30 g, 285 mmol), 4-vinylpyridine (40 g, 216 mmol) and acetic acid (12.9 g, 215 mmol) were mixed in ethanol (400 mL) and heated to reflux for 18 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in water and ethyl acetate and neutralized with satd NaHCO3. The layers were separated. The water layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography to provide 1-Boc-4-[2-(4-pyridinyl)ethyl]piperazine (55.9 g, 87%) as an off white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[CH:27]=[C:15]2[N:16]=[C:17]([CH3:26])[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:19]([Cl:20])[N:14]2[N:13]=1.C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Br:11][C:12]1[CH:27]=[C:15]2[N:16]=[C:17]([CH3:26])[C:18]([CH:21]([OH:36])[C:22]([O:24][CH3:25])=[O:23])=[C:19]([Cl:20])[N:14]2[N:13]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2cc(Br)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 2.83 mL, 1.413 mmol) in THF (6 mL) at −78° C. was added a solution of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (300 mg, 0.942 mmol) in THF (6 mL) dropwise over 20 min. The mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (369 mg, 1.413 mmol) in THF (6 mL) was added over 15 min and the reaction mixture was stirred for additional 60 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (4 mL). The reaction mixture was allowed to warm to room temperature and then diluted with ethyl acetate (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (85 mg, 27%). 1H NMR (400 MHz, CHLOROFORM-d) δ 2.63 (3 H, s), 3.84 (3 H, s), 5.74 (1 H, s), 6.71 (1 H, s).
Reaction SMILES: Br[C:2]1[S:19][C:5]2[C:6]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[F:20][C:21]1[C:26]([C:2]2[S:19][C:5]3[C:6]4[N:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:7]=4[O:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: COC(=O)c1cnc2c(c1)OCCc1cc(Br)sc1-2
Reactant: OB(O)c1cccnc1F
Product: COC(=O)c1cnc2c(c1)OCCc1cc(-c3cccnc3F)sc1-2
Yield: 61 %

Procedure:
Methyl 9-bromo-6,7-dihydrothieno[2,3-d]pyrido[3,2-b]oxepine-3-carboxylate was coupled with 2-fluoropyridin-3-ylboronic acid under Suzuki conditions to give methyl 9-(2-fluoropyridin-3-yl)-6,7-dihydrothieno[2,3-d]pyrido[3,2-b]oxepine-3-carboxylate. Yield 61%. MS (ESI+): 357.1
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[OH-].[NH4+].[H][H]>[Ni].C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccco1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccco1
Yield: 71.4 %

Procedure:
A mixture of ethyl 3-(2-furanyl)acrylate (46.7 g) and conc. ammonium hydroxide solution (25 ml) was hydrogenated in the presence of Raney Nickel (500 mg) at 35° C. until a theoretical amount of hydrogen was taken up. The Raney Nickel was removed by filtering through diatomaceous earth and the filtrate was evaporated at reduced pressure to yield a brown oil. The oil was dissolved in ethyl acetate, washed with distilled water, dried (MgSO4) and the solvent evaporated at reduced pressure to yield ethyl 3-(2-furanyl)-propionate (33.77 g) as a brown oil.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[C:20]([C:28]([O:30]C)=[O:29])=[CH:21][C:22]4[N:23]([N:25]=[CH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:32]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[C:20]([C:28]([OH:30])=[O:29])=[CH:21][C:22]4[N:23]([N:25]=[CH:26][N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc2ncnn2nc1NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2ncnn2nc1NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
1.58 g of methyl [6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[1,5-b]pyridazin-7-yl]carboxylate was dissolved in 10 ml of ethanol; 8.0 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 1.5 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and washed with ethyl acetate; 1 N hydrochloric acid was added to ajust pH 4.5. The mixture was saturated with saline and extracted with tetrahydrofuran; the extract was dried with magnesium sulfate. The crystal obtained by concentration under reduced pressure was washed with ethyl ether, collected by filtration and dried to yield 788 mg of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[N:27][N:26]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:27][N:26]=1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nnc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (300 mg, 0.94 mmol), 1,4-dichlorophthalazine (188 mg, 0.94 mmol) and N,N-diisopropylethylamine (410 μl, 2.36 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 18 hours. More 1,4-dichlorophthalazine (188 mg, 0.94 mmol) was added and the reaction stirred at room temperature for 36 hours, then heated at 55° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was washed with more aqueous sodium bicarbonate, brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 92:8:0.8 by volume) to provide the title compound (183 mg, 61%). LRMS APCI+ m/z 481 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:5]([O:7]CC)=O.[Cl:15][C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:15])[N:21]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: CCOC(=O)c1ccc(OC)c(Br)c1
Reactant: Cc1cccc(Cl)n1
Product: COc1ccc(C(=O)Cc2cccc(Cl)n2)cc1Br
Yield: 88.4 %

Procedure:
In a similar manner as described in Example 1 from ethyl 3-bromo-4-methoxybenzoate (13.6 g, 52.5 mmol) and 6-chloro-2-picoline (5.7 mL, 52.5 mmol), 1-(3-bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone (15.8 g, 88%) was obtained as a yellow solid (existing as a mixture of ketone and enol tautomers). 1H NMR (CDCl3) of the ketone: δ 8.27 (s, 1H), 8.02 (dd, 1H), 7.63 (t, 1H), 7.23 (m, 2H), 6.94 (d, 1H), 4.41 (s, 2H), 3.97 (s, 3H); MS m/z340 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[Cl:26])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:27][N:28](C=O)C>C(=O)(O)[O-].[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>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:27]#[N:28])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=2)=[O:12])[CH2:14][CH2:15]1
Reactant: CN(C)C=O
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)ccc2Cl)CC1
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: N#Cc1ccc2nnc(C(=O)N3CCC(c4cc(F)ccc4Cl)CC3)n2c1
Temperature: 130 °C
Yield: 26.1 %

Procedure:
A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl)piperidin-1-yl)methanone (50 mg, 0.21 mmol) in DMF (2.0 mL) zinc cyanide (48 mg, 0.41 mmol) was sparged with Ar for 20 min. To the solution was added Pd(PPh3)4 (13 mg, 0.011 mmol) and the vessel was sealed and heated to 130° C. with microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) and freeze dried to give 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (21 mg, 54%): mp 211-214° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.52-9.50 (m, 1H), 8.13 (dd, J=9.5, 1.0 Hz, 1H), 7.81 (dd, J=9.5, 1.5 Hz, 1H), 7.50 (dd, J=9.0, 5.5 Hz, 1H), 7.28 (dd, J=10.5, 3.5 Hz, 1H), 7.16-7.11 (m, 1H), 5.16-5.11 (m, 1H), 4.78-4.71 (m, 1H), 3.46-3.30 (m, 2H, overlaps with H2O), 3.11-3.01 (m, 1H), 1.99-1.70 (m, 4H); ESI MS m/z 384 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43]>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[O:34])[C:15]1=[O:38]
Reactant: CC(C)(CN)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Solvent: CCO
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 3-amino-2,2-dimethyl-1-propanol (0.008 mL, 0.078 mmol) for 20 min. (160° C. in a microwave vessel. The reaction was further microwaved for 40 min.@160° C., cooled to ambient temperature, and the resulting suspension was filtered, washed with EtOH and then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.57 (s, 6 H), 1.93 (s, 1 H), 2.91 (d, J=5.19 Hz, 2 H), 3.08 (d, J=5.62 Hz, 2 H), 3.92 (t, J=5.33 Hz, 2 H), 4.16 (s, 2 H), 4.56-4.68 (m, 3 H), 7.11-7.18 (m, 2 H), 7.35-7.41 (m, 2 H), 7.80 (s, 4 H), 8.22 (d, J=0.84 Hz, 1 H), 8.55 (d, J=0.56 Hz, 1 H), 10.02 (t, J=6.32 Hz, 1 H); ES+ MS: 573 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:33]=[C:31]([NH:30][C:26]4[CH:25]=[C:24]([OH:23])[CH:29]=[CH:28][CH:27]=4)[N:32]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: N=C(N)Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3cccc(O)c3)ncc1CC2
Yield: 0.8 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (210 mg, 7.94 mmol), N-(3-hydroxy-phenyl)-guanidine nitrate (170 mg, 7.94 mmol), NaOH (32 mg, 7.94 mmol), and 2-methoxyethanol (2 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (10% MeOH:EtOAc) gave the pure title product as a yellow solid (20 mg, 8%): mp 310° C. (dec). Anal. RP-HPLC: tR 10.3 min (0-60% MeCN, purity 92%). 1H-NMR (DMSO-d6): δ 9.50 (s, 1H, OH/NH), 9.28 (s, 1H, OH/NH), 8.38 (s, 1H, Py-H), 7.37 (t, 1H, J 2.3, Ph-H), 7.27 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 7.08 (t, 1H, J 8.3, Ph-H), 6.40 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 3.05 (m, 4H, CH2—CH2), 2.78 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 168.71, 159.05, 158.88, 157.42, 155.97, 155.20, 141.75, 128.81, 127.83, 115.89, 109.69, 108.35, 105.87, 24.72, 23.09, 19.38. MS (ESI+): m/z 311.06 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[O:21][C:22]1[C:23](=[O:32])[N:24]([CH3:31])[CH:25]=[CH:26][C:27]=1[C:28](Cl)=[O:29].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:28]([C:27]3[CH:26]=[CH:25][N:24]([CH3:31])[C:23](=[O:32])[C:22]=3[OH:21])=[O:29])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: COc1c(C(=O)Cl)ccn(C)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccc(C(=O)N[C@@H]2CC[C@H](c3ccc(Cl)c(Cl)c3)c3ccccc32)c(O)c1=O
Reaction time: 2 h

Procedure:
To a solution of cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (10 mg, 0.034 mmol) (Intermediate 16) and 3-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carbonyl chloride (Intermediate 12A) (6.90 mg, 0.034 mmol) in DCM (1 mL) was added Et3N (0.014 mL, 0.10 mmol). The reaction mixture was stirred for 2 h. The reaction mixture was quenched with H2O and DCM. The DCM portion was dried over Na2SO4, filtered and the solvent removed under reduced pressure to give Example 8A which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH3:16])=[CH:4][C:3]=1[OH:17].[CH2:18](Br)[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:18]([O:17][C:3]1[CH:4]=[C:5]([CH3:16])[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:2]=1[CH3:1])[CH2:19][CH2:20][CH3:21]
Reactant: Cc1cc(OCc2ccccc2)c(C)cc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(C)c(OCc2ccccc2)cc1C
Yield: 78.1 %

Procedure:
A mixture of 13.4 g (59 mmol) of 2,5-dimethyl-4-(phenylmethoxy)phenol (Example K), 9.7 g (1.2×59 mmol) of butyl bromide and 12.2 g (1.5×59 mmol) of anhydrous potassium carbonate in 150 mL of acetonitrile is stirred at reflux for 40 hours. The reaction flask and inorganic residue are washed with acetonitrile and the filtrate is evaporated. Chromatography on a 3.5 cm column containing 175 g of basic alumina (activity grade I) prepared in 2:1 hexane-toluene and elution with the same solvent affords 13.1 g of the title compound; bp 153°-155° C./0.50 mm (mp 185°-195° C).
Reaction SMILES: [Cl-].[Cl:2]C1N(C)CC[NH+]1C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCCl>[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:2])=[O:16])=[CH:13][CH:12]=1
Reactant: CN1CC[NH+](C)C1Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)c1ccc(O)cc1
Reaction time: 24 h
Yield: 72 %

Procedure:
To 9.72 g (0.0575 mole) of 2-chloro-1,3-dimethylimidazolinium chloride, 90 ml of 1,2-dichloroethane and 6.91 g (0.05 mole) of 4-hydroxybenzoic acid were added. To the mixture, 5.06 g (0.05 mole) of triethylamine was dropwise added over 30 minutes while maintaining the temperature of the mixture at 15°-20° C. Thereafter, the reaction was carried out at 15°-20° C. for 24 hours. The reaction mass was analyzed by gas chromatography and liquid chromatography. Unreacted 4-hydroxybenzoic acid remained 1.79 g (0.013 mole). 4-Hydroxybenzoyl chloride was obtained in the yield of 72%.
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4ccc(Oc5ccccc5)cc4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(O)cc(-c2c(-c3ccnc(-c4ccc(Oc5ccccc5)cc4)c3)cnn2CC#N)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (56.7 mg, 0.12 mmol) prepared in Example 42 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (34 mg, 61%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH:18]C(OC(C)(C)C)=O)=[N:16][C:12]=2[CH:11]=1)=[O:9].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH2:18])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNC(=O)OC(C)(C)C)n2C)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN)n2C)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4.81 g (0.10 mol) of 1-methyl-2-(N-tert-butoxycarbonylaminomethyl)benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide were dissolved in 25 mL of methylene chloride, mixed with 5 mL of trifluoroacetic acid and stirred for 5 hours at ambient temperature. Then the solvent was evaporated off and the residue was stirred with ether. The crystals thus formed were filtered off, washed with ether, and dried. Yield: 3.15 g (68% of theory), C20H23N5O3 (381.4); Rf value: 0.18 (silica gel; methylene chloride/ethanol=9:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:19][CH3:20])[C:16]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:22]#[N:21])=[CH:24][CH:25]=2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
(RS)-(4-Benzyloxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile to give (RS)-2-(4-benzyloxy-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide according to general procedure B. Colorless solid. MS 387.3 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)O[C:6](=[O:7])[C:5]2=[CH:12][C:13]=1[I:14].C(O)(=O)C.C(N)=[NH:20]>CN(C)C=O>[OH:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:13]([I:14])[CH:12]=2)[N:10]=[CH:9][N:20]=1
Reactant: N=CN
Reactant: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ncnc2cc(F)c(I)cc12
Temperature: 110 °C
Yield: 91.2 %

Procedure:
Dimethylformamide (0.5 liters), 4-fluoro-5-iodo-isatoic anhydride (45 grams, 147 mmoles), and formamidine acetate (45.92 grams, 441 mmoles), were combined in a one liter one-neck flask fitted with a magnetic stir bar. The mixture was placed under anhydrous nitrogen and heated at 110° C. for 6 hours. The mixture was allowed to cool, followed by concentrating the reaction mixture to one third its original volume on the rotary evaporator. The resulting mixture was poured onto 3 liters of ice water. The resulting precipitated solid was collected by suction filtration. The solid was washed with an additional one liter of distilled water. The resulting solid was dried under vacuum at 70° C. to yield 38.9 grams (91%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 12.43(s, 1H), 8.46(d, 1H), 8.12(s, 1H), 7.49(d, 1H). ESI-MS m/z 291 (M+1).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][C:16]1[C:17]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1>O1CCOCC1>[Cl:25][C:23]1[CH:22]=[CH:21][C:18]2[S:19][CH:20]=[C:16]([CH2:15][N:1]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[C:2]3=[O:3])[C:17]=2[CH:24]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1C(=O)N(Cc2csc3ccc(Cl)cc23)c2ccccc21
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 25 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0° C. under argon. The mixture was allowed to stir for 5 minutes and then a solution of 3-(bromomethyl)-5-chlorobenzo[b]thiophene (267 mg, 1.02 mmol) in dioxane (10 mL) was added dropwise to the reaction mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified by preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (125 mg, 0.38 mmol, 45%). 1H NMR (400 MHz): δ 7.89 (s, 1H), 7.79 (d, J=8.5, 1H), 7.65 (d, J=7.5, 1H), 7.54 (t, J=8.0, 1H), 7.42 (s, 1H), 7.38. (d, J=8.5, 1H), 7.14 (t, J=7.5, 1H), 6.88 (d, J=7.8, 1H), 5.13 (s, 2H).