Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(Cl)(Cl)Cl>[C:17]([N:7]1[CH2:8][CH2:9][CH2:10][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: c1cc2c(s1)CNCCC2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCCc2ccsc2C1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a mixture of 4 g of 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine and 4 g of pyridine in 20 ml of chloroform was added 4.1 g of acetic anhydride under ice-cooling and the mixture was stirred at room temperature for an hour. The mixture was poured into water and extracted with chloroform. The extract was washed with water, dried and concentrated to give 4 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17]O)[CH:15]=3)[N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:37])(=O)=O.C(OCC)(=O)C>C(Cl)Cl>[Cl:37][CH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under ice-cooling, to a solution of 3.0 g of tert-butyl 3-(3-fluorophenyl)-5-(hydroxymethyl)-1H-1-indazolecarboxylate in 30 ml methylene chloride were added 1.6 ml of triethylamine and 0.78 ml of methanesulfonyl chloride, and the mixture was stirred at room temperature for one day. To the reaction mixture was added 180 ml of ethyl acetate, and the mixture was sequentially washed with water, 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (toluene), to give 2.74 g of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH:6]1[CH2:9][CH2:8][C:7]1=O.[NH2:17][CH2:18][CH2:19][OH:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C@H:6]1[CH2:9][CH2:8][C@H:7]1[NH:17][CH2:18][CH2:19][OH:20]
Reactant: O=C1CCC1Oc1ccccc1C(F)(F)F
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OCCN[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of C4 (3.5 g, 15 mmol) and 2-aminoethanol (1.03 g, 16.8 mmol) in 1,2-dichloroethane (100 mL) was treated with sodium triacetoxyborohydride (5.62 g, 25.2 mmol) and stirred at room temperature for 2 hours. The reaction was treated with acetic acid (4 mL) and stirred at room temperature for 16 hours. Aqueous sodium hydroxide solution (1 N, 100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 70% [10% 2 N ammonia in methanol/90% ethyl acetate] in ethyl acetate) afforded the title compound as a light amber oil. Yield: 2.1 g, 7.6 mmol, 51%. The indicated cis stereochemistry was tentatively assigned, based on NOE (nuclear Overhauser enhancement) experiments. 1H NMR (400 MHz, CDCl3) δ 7.57 (br dd, J=7.7, 1.3 Hz, 1H), 7.41-7.47 (m, 1H), 6.99 (br dd, J=7.6, 7.6 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 4.88-4.93 (m, 1H), 3.54-3.66 (m, 3H), 2.81-2.88 (m, 1H), 2.63-2.70 (m, 1H), 2.22-2.31 (m, 1H), 1.97-2.16 (m, 2H), 1.86-1.94 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:37][CH2:36][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]5[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]=5)[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:45]1(C)C=CC=CC=1B(O)O>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:33][CH2:34][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:36][CH2:37]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[CH3:45])[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Cc1ccccc1B(O)O
Reactant: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccc(C)cc1
Product: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1C

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-(4-methylphenyl)-1,3-thiazol-2-amine was used to convert o-tolylboronic acid (0.200 g, 1.47 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.8-11.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-(2-methylphenyl)-1,3-thiazol-2-amine as an off-white solid (0.075 g, 0.123 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.83 min; MS (MH)+ 608.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:18]([O-])=O)[C:8]([O:16][CH3:17])=[C:9]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:18][C:7]1[C:8]([O:16][CH3:17])=[C:9]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1C(C)(C)C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1C(C)(C)C#N
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a solution of 2-(5-tert-butyl-2-methoxy-3-nitrophenyl)-2-methylpropanenitrile (0.086 g, 0.311 mmol) in ethanol (3.1 mL), iron (0.087 g, 1.56 mmol), ammonium chloride (0.083 g, 1.56 mmol) and water (1.6 mL) were added, and the mixture was stirred for 3 hours under reflux. The reaction mixture was filtered and washed with ethanol. The obtained filtrate was evaporated under reduced pressure and the residue was dissolved in dichloromethane. After washing this solution with water and then saturated brine, the solution was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-30/70) to obtain 0.051 g of the captioned compound (67% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[CH:20]=[C:19]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2ccc(Cl)nn2)cn1
Temperature: 70 °C
Yield: 46.3 %

Procedure:
A mixture of 3,6-dichloro-pyridazine (1.06 g, 6.98 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.47 g, 5.0 mmol) in 2.0 M potassium carbonate (10 mL, 20 mmol) and 1,4-dioxane (40 mL) was degassed by house vacuum for 15 min followed by bubbling with argon for ˜10 min, Peppsi-ipr (340 mg, 0.5 mmol) was then added. After flushing with argon for another ˜10 min, the mixture was heated at 70° C. for 4 h and allowed to cool to room temperature. The solid was removed by filtration through Celite, and the filtrate was separated. The aqueous solution was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, concentrated, and purified by column to provide 0.65 g desired product (46%). 1H NMR (DMSO) δ 9.08 (s, 1H), 8.47 (s, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 1.59 (s, 3H); MS (ES) m/z 280.8(M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:24][CH3:25].[CH2:26]([CH2:30][C:31](=O)[CH3:32])[C:27]([CH3:29])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.ClCCl>[CH3:32][C:31]1[N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[CH:4][C:3]=2[O:24][CH3:25])[C:27]([CH3:29])=[CH:26][CH:30]=1
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-n1c(C)ccc1C
Temperature: 25 °C

Procedure:
A solution of (4-amino-3-methoxy-phenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone prepared in the manner of Albright et al., E.P.636625-A2 (0.675g, 2 mmol) and acetonyl acetone (0.3 mL, 2.5 mmol) in benzene (100 mL) was treated with a crystal of para-toluenesulfonic acid. The stirred solution was warmed to reflux for 46 hrs using a Dean Stark trap. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate then water. The residue (oil, 0.900 g) was flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to yield 0.610 g of the title compound as a white foam. Recrystallization of a sample of this material yielded yellow crystals, m.p. 141–144° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]([NH:11]C(=O)COC)[CH2:3][CH2:2]1.[ClH:17]>C(O)C>[ClH:17].[NH2:11][C@H:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1
Reactant: COCC(=O)N[C@@H]1CCOc2ccccc21
Agent: Cl
Solvent: CCO
Product: N[C@@H]1CCOc2ccccc21

Procedure:
A solution of the above N-[(4R)4-chromanyl]-2-methoxyacetamide (2.2 g, 0.0325 mol) in ethanol (100 ml) and concentrated hydrochloric acid (30 ml) was heated at reflux for 12 hours, then evaporated. A small amount of ethyl acetate was added to the residue and the solid filtered off to give (4R)4-aminochromane hydrochloride (2.3 g), m.p. 261-263° C., chemical purity>95%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26](O)(=[O:35])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C>>[C:29]1([CH2:28][CH2:27][C:26]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)CCc4ccccc4)c3)c2c1
Yield: 14.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with hydrocinnamic acid (0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 31 mg (13% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4-7.1 (m, 5H), 2.95 (t, 2H), 2.68 (t, 2H); ES-MS (m/z) 385 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[N+:20]([O-])([O-:22])=[O:21].[K+].[OH-].[Na+]>C(OCC)C.O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:20]([O-:22])=[O:21])=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccccc1N1CCNCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 57.7 %

Procedure:
63 mL of 5 M sulphuric acid were dropwise added to 60 g of commercially available 1-(2-methoxyphenyl)-piperazine (312 mmol) within 30 minutes at 0° C., followed by the addition of 306 mL of concentr ated sulphuric acid. The mixture was stirred for 90 minutes. Then 25.2 g of potassium nitrate (249.65 mmol) were added in portions within 1 h. After stirring for 3 h, another 3.16 g of potassium nitrate (31.2 mmol) were added. When the reaction was complete, the mixture was poured onto 1 kg of ice water and the pH was adjusted to pH 12 with aqueous sodium hydroxide. 300 mL of water were added, the aqueous phase was extracted three times with 300 mL of ethyl acetate each. The organic phases were combined, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 48.7 g of crude product. This material was dissolved in a small amount of diethyl ether. Crystallization started upon scratching the glass surface. The residue was filtered, washed with cold diethyl ether, and dried to yield 34.2 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:56][C:57]([CH2:59][CH2:60][CH:61]([NH2:72])[C:62]1[NH:66][C:65]2[CH:67]=[CH:68][C:69]([Cl:71])=[CH:70][C:64]=2[N:63]=1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[CH2:49]([O:56][C:57]([CH2:59][CH2:60][CH:61]([NH:72][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:62]1[NH:66][C:65]2[CH:67]=[CH:68][C:69]([Cl:71])=[CH:70][C:64]=2[N:63]=1)=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: NC(CCC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NC(CCC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 70 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 3-benzyloxycarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)propylamine in tetrahydrofuran. Yield: 70%; Rf value: 0.24 (silica gel; ethyl acetate/ethanol=95:5); C31H31ClN4O4 (559.06); mass spectrum: (M+H)+=559/561 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](I)[CH:5]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)[C:7]([CH3:10])=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1ccc(C)c(I)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-c2ccc(C#N)cc2)c1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask containing 3-iodo-4-methyl-benzoic acid methyl ester (1.38 g, 5.00 mmol), 4-cyanophenylboronic acid (1.10 g, 7.48 mmol), palladium acetate (168 mg, 0.748 mmol), 2-(dicyclohexylphosphino)biphenyl (0.526 g, 1.50 mmol) and potassium fluoride (0.870 g, 15.0 mmol) is added anhydrous 1,4-dioxane (15 ml). The flask is purged with argon and sealed. The mixture is stirred at 130° C. for 18 hours, cooled to ambient temperature and then water (20 ml) and ethyl acetate (20 ml) are added. Solid is removed under vacuum filtration. The filtrate is extracted with EtOAc (20 ml×2). The organic layers are combined, washed with aqueous HCl (5%, 20 ml) and saturated NaHCO3 (20 ml). It is dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography (EtOAc/Hexane, gradient) to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid methyl ester 2; LC-MS m/z: 252.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[C:13]([C:23]([OH:25])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]2[C:34]3([CH2:40][O:41][C:30]=2[CH:29]=1)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[C:13]([C:23]([N:37]3[CH2:38][CH2:39][C:34]4([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=5[O:41][CH2:40]4)[CH2:35][CH2:36]3)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Reactant: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 64.3 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(3-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.382 mmol) obtained in step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.087 g, 0.420 mmol), the title compound (0.130 g, 64%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[C:13]3[C:14]([CH3:34])=[C:15]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:36])[CH3:35])=[CH:5][CH:4]=1>C(O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH2:22][CH2:21][N:20]([C:15]3[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]4[O:11][C:10]([CH3:36])([CH3:35])[CH:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[C:13]=4[C:14]=3[CH3:34])[CH2:25][CH2:24]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(OC)cc3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(C2c3c(C)c(N4CCN(c5ccc(OC)cc5)CC4)c(C)c(C)c3OC2(C)C)cc1
Yield: 88 %

Procedure:
Using 3-(4-methoxyphenyl)-5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 66, the title compound was synthesized in the same manner as in Example 46. Yield 88%. mp. 205–207° C. (ethanol).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[CH:2]=1.C(O)[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O.C(O)(=O)C.[Na].NCC(O)=O>>[CH:5]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=[C:3]([OH:10])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Agent: NCC(=O)O
Agent: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
To determine the influence of the temperature on the enzyme activity 25 μl enzyme solution was added to 225 μl of a solution containing 0.1% p-nitrophenyl-β-D-cellobioside and 25 mM gluconolactone in a 50 mM sodium acetic acid buffer at pH 5.0. Following an incubation of 15 minutes at 30, 40, 50, 60 or 70° C. the enzyme activity was stopped by adding 750 μl of a 0.5 M glycine buffer pH 9.0. The concentration of p-nitrophenol formed was determined spectrophotometrically at 400 nm.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][OH:19]>>[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCc1nccs1
Product: O=C(O)c1ccc(OCc2nccs2)nc1
Temperature: 50 °C
Yield: 21 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 21% yield starting from ethyl 6-chloronicotinate and 1,3-thiazol-2-ylmethanol. The deprotonation step was performed at ambient temperature and the intermediate product was purified by column chromatography using a gradient of ethyl acetate in heptane. The reduction step was carried out in sodium hydroxide:ethanol 50/50 heated to 50° C. for 1.5 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (d, 1 H), 8.21 (dd, 1 H), 7.83 (d, 1 H), 7.76 (d, 1 H), 7.04 (d, 1 H), 5.74 (s, 2 H); MS (APPI/APCI) m/z 237[M+H+].
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][CH2:3]1.[H-].[Na+].[CH3:15][O:16][CH2:17][CH2:18][CH2:19]Br>CN(C=O)C>[OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH2:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:3]1
Reactant: COCCCBr
Reactant: O=S1(=O)NCC(O)c2ccsc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1CC(O)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
The product from Example 1, Step C (2.0 g, 9.74 mmol) was added to a suspension of sodium hydride (0.4 g, 10.0 mmol, of a 60% suspension in mineral oil) in DMF (30 ML) and the mixture was stirred for 1hr. then cooled to 0° C. 3-Bromopropyl methyl ether (1.5 g, 9.74 mmol) was added and the mixture was stirred overnight then quenched with water (200 mL), and extracted with ethyl acetate (4×30 mL). The extracts were combined, washed with water (100 mL), dried (MgSO4) and concentrated under reduced pressure which provided an oil which was purified by column chromatography (silica, gradient: hexane to ethyl acetate) to give 1.7 g (63%) of a clear oil which was not purified further.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]([CH3:24])[C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH:9]=[C:10]([C:11]([O:13]C)=[O:12])[C:5]2=[N:4][N:3]=1.[Li+].[OH-]>CO>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]([CH3:24])[C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:5]2=[N:4][N:3]=1
Reactant: COC(=O)c1cc(N(C)[C@@H](C)c2ccccc2)nn2c(C)nnc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnc2c(C(=O)O)cc(N(C)[C@@H](C)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A mixture of compound (S)-methyl 3-methyl-6-(methyl (1-phenylethyl) amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (400 mg, 1.22 mmol) and LiOH (88 mg, 3.66 mmol) in MeOH (15 mL) was stirred at room temperature for 0.5 h and then concentrated in vacuum. The residue was dissolved with DCM (100 mL), adjusted pH to 3 with 2 N aq. HCl and washed with brine (20 mL). The organic layer was evaporated in vacuum to give product (S)-3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid as a yellow solid (330 mg, 85%). 1H NMR (300 MHz, CDCl3) δ: 7.95 (s, 1H), 7.29˜7.42 (m, 5H), 5.83˜5.85 (s, 1H), 2.98 (s, 3H), 2.70 (s, 3H), 1.70 (d, 3H, J=6.6 Hz). LRMS (M+H+) m/z: calcd 312; found 312.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:1][N:2]([C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1
Reactant: CCOC(=O)CCc1ccc(OCCCBr)cc1
Reactant: CNc1nc(-c2ccccc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCCCN(C)c2nc(-c3ccccc3)cs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To an ice-cooled solution of N-methyl-4-phenyl-2-thiazolamine (0.30 g, 1.7 mmol) in N,N-dimethylformamide (5 mL) was added 60% sodium hydride (72 mg, 1.8 mmol), and the mixture was stirred for 30 min. Ethyl 4-[(3-bromopropyl)oxy]benzenepropanoate (0.57 g, 1.8 mmol), was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=15:1) to give the title compound (0.58 g, yield 80%). oil.