Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:24][C:25]([F:42])([F:41])[C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38]CO)[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17][CH2:18][CH2:38][N:35]3[CH2:34][CH2:33][N:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:42])([F:24])[F:41])[CH:27]=4)[CH2:37][CH2:36]3)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Product: O=C(OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Yield: 6.1 %

Procedure:
Using the procedure of Example 3, 4 g of the ester of Example 1 and 3.316 g of 2-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethanol were reacted to obtain 6.88 g of a raw oily product. 500 mg of the said product were crystallized from isopropyl ether to obtain 425 mg of 2-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethyl 2-(7-chloro-4-quinolinylamino)-5-fluoro-benzoate melting at 113° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>C(#N)C>[CH2:29]([O:20][C:6]1[C:5]([O:21][CH3:22])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19])[CH3:30]
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC)c1OC
Temperature: 80 °C
Yield: 45.7 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (90 mg, 0.302 mmol) in acetonitrile was added potassium carbonate (126 mg, 0.906 mmol) and ethyl iodide (141 mg, 0.906 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded title compound as a solid (45 mg, 46%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.C1(C)C=CC=CC=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O.[OH-].[Na+].CCO>[F:26][C:27]([F:38])([F:39])[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)[CH:3]=2)=[CH:31][CH:30]=1
Reactant: Clc1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)Oc1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)cc1
Temperature: 140 °C

Procedure:
To a 5-mL, microwave vial containing 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (0.30 g, 1.2 mmol) and 1:1 toluene:EtOH (2.5 mL) was added 4-trifluoromethoxyphenylboronic acid (0.30 g, 1.9 mmol, Aldrich), 2 N potassium carbonate (2.5 mL), and palladium(0)-tetrakis-triphenylphosphine (0.070 g, 0.060 mmol, Strem Chemical). The reaction mixture was heated at 140° C. for 10 min in a microwave synthesizer, allowed to cool to room temperature and diluted with water (5 mL) and 1 N sodium hydroxide (50 mL). The product was extracted with dichloromethane (2×100 mL), dried over sodium sulfate, and concentrated in vacuum. The crude material was purified by silica gel chromatography (gradient: 1–1.7% 2 N ammonia in methanol/dichloromethane) to obtain the title compound as a white solid. Mp: 67–168° C. MS (ESI, pos. ion.) m/z: 384 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2([CH2:14][O:15][CH3:16])[CH2:13][O:12][CH2:11]2)=[C:6]([O:17][CH3:18])[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[C:34](=[O:38])[O:33][CH2:32]3)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][O:17][C:6]1[C:7]([O:8][CH2:9][C:10]2([CH2:14][O:15][CH3:16])[CH2:13][O:12][CH2:11]2)=[C:2]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[C:34](=[O:38])[O:33][CH2:32]3)[CH:3]=[CH:4][C:5]=1[O:19][CH3:20]
Reactant: COCC1(COc2c(Br)ccc(OC)c2OC)COC1
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COCC1(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC)c2OC)COC1
Temperature: 120 °C

Procedure:
3-(6-Bromo-2,3-dimethoxy-phenoxymethyl)-3-methoxymethyl-oxetane (0.02 g, 0.06 mmol) and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one (Compound 309) (0.039 g, 0.14 mmol) were dissolved in 1,4-dioxan (0.6 mL). Argon was purged through the solution. Pd2(dba)3 0.001 g, 0.001 mmol) and PCy3 (0.0008 g, 0.003 mmol) were added followed by addition of K3PO4 (0.043 g, 0.2 mmol) in H2O (0.3 mL). The reaction mixture was heated in a microwave oven at 120° C. for 10 min. The mixture was filtrated, concentrated, redissolved in DMSO and purified by preparative HPLC to afford the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[CH:9][CH:8]=1.O>CN(C)C=O>[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([C:18]3[NH:19][N:3]=[N:2][N:1]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2ccc(COc3cccc(-c4nnn[nH]4)c3)cc2)cc1
Temperature: 125 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To a mixture of sodium azide (2.37 g, 36.45 mmol) and ammonium chloride (1.95 g, 36.45 mmol) in dry N,N-dimethylformamide (100 mL) under an atmosphere of nitrogen, 3-(biphenyl-4-ylmethoxy)benzonitrile (8.0 g, 28.04 mmol) was added and the reaction mixture was stirred at 125° C. for 18 hours. To the cooled reaction mixture water (100 mL) was added and the reaction mixture stirred for 0.75 hour. The precipitate was filtered off and washed with water, 96% ethanol (2×50 mL), and dried in vacuo at 50° C. for 18 hours affording 5.13 g (56%) of the title compound.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.[OH-].[Na+].O>CO>[CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:24][NH2:25])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCCCCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCOc1ccc(CC(CN)c2ccc(F)cc2)cc1
Reaction time: 12 h
Yield: 20 %

Procedure:
A solution of 51.5 g of 4-hexyloxybenzaldehyde and 33.8 g of 4-fluorophenylacetonitrile in methanol was stirred at room temperature and aqueous sodium hydroxide (50 percent) was added dropwise until a precipitate appeared. Water was then added and the solids were collected by filtration to render α-[[4-(hexyloxy)phenyl]methylene]-4-fluorophenylacetonitrile which was reduced as follows. 40.2 g of said nitrile, 10 g of Raney nickel, 150 ml of anhydrous ammonia and 300 ml of tetrahydrofuran were stirred at 110° for 12 hours at a pressure of 2000 psi. The catalyst and solvent were removed and the hydrochloride salt was made in the filtrate by the addition of anhydrous hydrochloric acid. Recrystallization from methanol rendered the title compound (20 percent yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cccnc1
Product: COC(=O)c1c(O)c2ccc(-c3cccnc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-pyridin-3-yl-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 3-pyridyl-boronic acid under conditions analogous to Example 14(a). MS ESI(+) m/e: 314.12 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.C1(P(C2C=CC=CC=2)(O[NH2:24])=O)C=CC=CC=1.O>O1CCCC1.CN1CCCC1=O>[NH2:24][N:5]1[CH:6]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:8]=[C:4]1[CH3:3]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(-c2ccccc2)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccccc2)cn1N
Temperature: 25 °C

Procedure:
7.92 g (171 mmol) of sodium hydride (55-60 percent dispersion in oil) are washed with absolute tetrahydrofuran. A solution of 13.2 g (83 mmol) of 2-methyl-4-phenylimidazole in 356 ml of N-methylpyrrolidone is added dropwise at 0°. The mixture is subsequently stirred at room temperature until the evolution of gas is no longer observed. 39.6 g (171 mmol) of O-diphenylphosphinylhydroxylamine are added portionwise thereto and the mixture is stirred for a further 18 hours. 400 ml of water are added thereto. The mixture is stirred for 1 hour and extracted four times with 1300 ml of methylene chloride each time. The extract is dried over sodium sulphate and evaporated. The residue is place on a column loaded with 700 g of silica gel (particle size 0.063-0.200 mm) amnd the product is eluted with methylene chloride/ethanol (98:2). The oil (N-amino-2-methyl-4-phenylimidazole) obtained after concentration is dissolved with 1150 ml of methylene chloride and treated with 13.94 g (60 mmol) of O-diphenylphosphinylhydroxylamine. After stirring for 3 days a further 13.94 g (60 mmol) of O-diphenylphosphinylhydroxylamine are added thereto and the mixture is stirred for a further 24 hours. The mixture is concentrated and the residue is placed on a column loaded with Amberlite IRA 400 (chloride). Elution is carried out with water. The aqueous solution is evaporated and the residue is placed on a column loaded with 300 g of silica gel (particle size 0.063-0.200 mm). The product is eluted with methylene chloride/ethanol (1:9). From the eluate there is obtained 1,3-diamino-2-methyl-4-phenylimidazolium chloride of melting point 162°-163°.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:8]=2[CH:7]=1)([OH:3])=[O:2].[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[C:1]([CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]([S:13](=[O:15])(=[O:14])[NH2:16])=[CH:12][C:8]=2[CH:7]=1)([O:3][CH2:19][CH3:20])=[O:2]
Reactant: CCO
Reactant: NS(=O)(=O)c1cc2cc(OCC(=O)O)ccc2s1
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 5 h
Yield: 87 %

Procedure:
A mixture of 5-(carboxymethoxy)benzo[b]thiophene-2-sulfonamide (1.50 g, 0.0052 m) in ethanol (15 ml) and concentrated sulfuric acid (3 ml) was refluxed with stirring for 5 hours. Ethanol was evaporated under reduced pressure, the residue was treated with H2O (25 ml) and extracted with ethyl acetate (50 ml and 2×25 ml). The combined extracts were washed with H2O, saturated sodium bicarbonate solution (2×25 ml), and three times with H2O. After drying over Na2SO4, the solvent was evaporated under reduced pressure to afford 1.43 g (87%) of product. Recrystallization from nitromethane afforded 1.12 g of analytically pure product melting at 167.5°-168° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:43]1([CH2:49][CH:50]=O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(O)(=O)C>ClC(Cl)C>[C:43]1([CH2:49][CH2:50][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH:2]2[CH2:11][NH:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3[C:25]([O:27][CH3:28])=[O:26])=[O:14])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3)cccc21
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3CCc3ccccc3)cccc21
Yield: 79.1 %

Procedure:
The product from Example 22B (0.2486 g, 0.50 mmol) and sodium triacetoxy borohydride (0.2235 g, 1.05 mmol) were suspended in dichloroethane (10 mL). The reaction flask was equipped with stir bar and spetum, then flushed with N2. Phenylacetaldehyde (0.10 mL, 0.85 mmol) was added followed by glacial acetic acid (0.2 mL, 3.4 mmol). After 1 hour of stirring at ambient temperature, the reaction mixture was quenched with water (20 mL) then partitioned between ethyl acetate/water. The aqueous phase was extracted with ethyl acetate (2×15 mL). The combined organic fractions were washed sequentially with aqueous saturated NaHCO3 (1×25 mL), water (1×25 mL), and brine (1×25 mL), dried (MgSO4), filtered and concentrated in vaco. The crude material was purified via column chromatography (2% to 5% methanol/dichloromethane) to afford the titled compound (0.1913 g, 79%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.99 (s, 1 H) 8.43 (s, 1 H) 7.80 (d, J=7.80 Hz, 1 H) 7.69 (d, J=8.48 Hz, 1 H) 7.48 (t, J=8.14 Hz, 1 H) 7.25 (m, 5 H) 7.04 (m, 1 H) 6.95 (d, J=7.46 Hz, 1 H) 6.71 (d, J=8.14 Hz, 1 H) 6.51 (t, J=6.95 Hz, 2 H) 4.03 (s, 3 H) 3.72 (m, 1 H) 3.37 (m, 3 H) 3.13 (m, 1 H) 2.82 (m, 3 H) 2.59 (m, 1 H) 1.89 (m, 1 H) 1.55 (m, 1 H). MS (ESI) m/z 484 (M+H)+, 482 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:64][CH3:65])=[C:6]([C@@:8]2([F:63])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][CH:23]3[C@H:28]([O:29]CC4C=CC=CC=4)[C@@H:27]([O:37]CC4C=CC=CC=4)[C@@H:26]([O:45]CC4C=CC=CC=4)[C@@H:25]([CH2:53][O:54]CC4C=CC=CC=4)[O:24]3)[C:9]2=[O:62])[CH:7]=1.C(O)C>[Pt]=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:64][CH3:65])=[C:6]([C@@:8]2([F:63])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][CH:23]3[C@H:28]([OH:29])[C@@H:27]([OH:37])[C@H:26]([OH:45])[C@@H:25]([CH2:53][OH:54])[O:24]3)[C:9]2=[O:62])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2cc(C(F)(F)F)ccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2cc(C(F)(F)F)ccc21
Reaction time: 144 h

Procedure:
To a round bottom flask containing a solution of 3-(S)-(5-Chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1-(3-(R),4-(S),5-(S)-tris-benzyloxy-6-(R)benzyloxymethyl-tetrahydro-pyran-2-yloxymethyl)-1,3-dihydro-indol-2-one; (3-(S)-VI) (0.768 g, 0.84 mmol) in 1:1 ethanol:ethyl acetate (6 mL) was added platinum oxide (0.095 g, 0.42 mmol). The reaction was allowed to run at room temperature under a hydrogen atmosphere for 6 days. Once complete, the reaction was filtered through a bed of celite and purified via reverse phase column chromatography (C18, 1:1 water:acetonitrile). The title compound was isolated as a white solid (0.279 g, 60%). 1H NMR (MeOH-D4, 400 MHz): δ 7.74 (m, 2H), 7.59 (d, 2H, J=8.8 Hz), 7.41 (m, 4H), 7.30 (dd, 2H, J=5.5 Hz, 2.3 Hz), 6.96 (m, 2H), 5.62 (d, 1H, J=10.8 Hz), 5.55 (d, 1H, J=11.3 Hz), 5.48 (d, 1H, J=10.8 Hz), 5.39 (d, 1H, J=11.2 Hz), 5.07 (d, 1H, J=3.8 Hz), 4.50 (d, 1H, J=7.8 Hz), 3.87 (dd, 1H, J=10 Hz, 1 Hz), 3.68 (m, 4H), 3.54 (d, 6H, J=2.6 Hz), 3.51 (d, 1H, J=4.6 Hz), 3.45 (d, 1H, J=3.8 Hz), 3.43 (d, 1H, J=3.8 Hz), 3.38 (m, 1H), 3.33 (m, 2H), 3.24 (m, 1H ); LRMS: 569 [M+NH4]+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](=[NH:10])[O:8][CH3:9].[CH2:15](O)[CH2:16][CH2:17]C>>[OH:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](=[NH:10])[O:8][CH2:9][CH2:15][CH2:16][CH3:17]
Reactant: CCCCO
Reactant: COC(=N)c1sc2ccccc2c1O
Product: CCCCOC(=N)c1sc2ccccc2c1O

Procedure:
A solution of 12 g of methyl 3-hydroxy-benzo[b]thiophene-2-carboximidate (Example 1) in 300 m. of anhydrous n-butanol is heated under reflux for 4 hours and then concentrated to yield upon crystallization from ethyl acetate solution yellow crystals having an m.p. of 185° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:22][C@H:23]1[CH2:27][C:26](=[O:28])[O:25][C:24]1=[O:29].C(O)(=O)C>C1COCC1.CCCCCC>[CH3:22][C@H:23]([C:24](=[O:29])[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)[CH2:27][C:26]([OH:28])=[O:25]
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Reactant: C[C@H]1CC(=O)OC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: C[C@@H](CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
400 mg (1.46 mmol) 6-bromo-2-phenyl-benzoxazole are dissolved in 15 ml THF and cooled to −70° C., and 1.22 ml (1.92 mmol) n-butyl lithium 1.6M in hexane are added dropwise. This solution chilled to −70° C. is added dropwise to an equally cold −70° C. solution of 220 mg (1.93 mmol) (S)-3-methyl-dihydro-furan-2,5-dione and 15 ml THF. After 15 min stirring the mixture is poured onto semisaturated, acetic acid-containing saline solution and extracted with EA. The org. phase is concentrated by rotary evaporation i. V. and the residue is separated through silica gel (eluant DCM/EA/glacial acetic acid).
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[N:10][C:9]([CH3:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].Cl>N1C=CC=CC=1>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:3]3[CH:11]=[N:10][C:9]([CH3:12])=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cc2ncnc(O)c2cn1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc2ncnc(Nc3cccc(Cl)c3)c2cn1
Yield: 34 %

Procedure:
Utilizing a procedure analogous to that described in Example 16, this product was prepared in 34% yield from 4-hydroxy-7-methyl-pyrido[4,3-d]pyrimidine (1.0 eq) and m-chloroaniline (40.0 eq) in pyridine. The HCl salt was generated from the purified free base according to the procedure given in Example 1. (M.P. 255-256° C.; GC-MS: 270 (MH+); anal. RP18-HPLC RT: 4.05 min.)
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](O)(=[O:33])[CH:30]=[CH:31][CH3:32]>>[C:29]([N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17]3[N:16]([N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:25]=3[C:26]([NH2:28])=[O:27])[C:20]=2[CH2:21]1)(=[O:33])[CH:30]=[CH:31][CH3:32]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCNC3
Reactant: CC=CC(=O)O
Product: CC=CC(=O)N1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1

Procedure:
The desired compound was prepared from 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide and but-2-enoic acid according to the procedure similar to that for compound 54. 1H NMR (400 MHz, DMSO-d6) δ 11.78-11.71 (m, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.46-7.39 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.11-7.04 (m, 4H), 6.73-6.63 (m, 2H), 4.80-4.71 (m, 2H), 3.90 (s, 2H), 2.76-2.70 (m, 2H), 1.88-1.86 (m, 3H). MS (ESI) m/e [M+1]+ 441.9.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][C:12](=[O:33])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][C:12](=[O:33])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)NCc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(CNC(=O)CNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10.5 g (0.0225 M) of benzyl{[[2-(o-fluorobenzoyl)-4-nitrophenyl]methylcarbamoyl]methyl}carbamate dissolved in 150 ml of glacial acetic acid are treated with 23 g of stannous chloride and 30 ml of a mixture of concentrated hydrochloric acid and water (1:1). The mixture is stirred at room temperature for 20 hours, poured on to ice/ammonia and extracted several times with ethyl acetate. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is purified on a 350 g silica gel column using methylene chloride/ethyl acetate as the eluting agent and crystallised from methylene chloride/ether. There is obtained benzyl{[[4-amino-2-(o-fluorobenzoyl)phenyl]methylcarbamoyl]methyl}carbamate which melts at 83° C.
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:23](Cl)(=[O:25])[CH3:24].O>C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 32 mL reaction vial was placed a stir bar, Et3N (0.5 mL) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.3 g) dissolved in 10 mL anhydrous THF. Acetic acid chloride (0.48 g) was added dropwise through a syringe at 0° C. The mixture was stirred 2 hrs at room temperature. After worked up with H2O at 0° C., it was extracted with EtOAc. The organic extracts were washed with 2M NaOH solution, NaHSO4 and saturated NaCl solution. After dried over Na2SO4, it was concentrated to give crude 4-(acetylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3, 400 MHz) δ 1.14 (m, 2H), 1.45 (s, 9H), 1.65 (m, 2H), 1.68 (m, 1H), 1.99 (s, 3H), 2.66 (m, 2H), 3.14 (m, 2H), 4.12 (m, 2H), 5.51 (m, 1H). Exact mass calculated for C13H24N2O3 256.18, found 257.4 (MH+).