Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C=C.O.[C:29]([OH:33])(C)(C)C>C(O)(C)(C)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].CC[C@H]1[C@@H]2C[C@H]([C@H](OC3C=CC(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@@H](CC)[C@@H](CC5)C4)=C4C(C5C(C(=O)C=34)=CC=CC=5)=O)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>[CH2:21]([O:20][C:11]1[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:7][CH:1]([OH:4])[CH2:29][OH:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)O
Reactant: C=CCc1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: CC[C@@H]1CN2CC[C@H]1C[C@@H]2[C@H](Oc1ccc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@H]3CC)c2c1C(=O)c1ccccc1C2=O)c1ccnc2ccc(OC)cc12
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1cccc(CC(O)CO)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a suspension of potassium ferricyanide (57.00 g, 0.173 mol), potassium carbonate (24.00 g, 0.174 mol), hydroquinine anthraquinone-1,4-diyl diether (0.495 g, 0.578 mmol), and potassium osmate dihydrate (0.043 g, 0.117 mmol) in water:tert-butyl alcohol (1:1, 600 mL) cooled to 0° C. was slowly added via an addition funnel a solution of 1-allyl-2-(benzyloxy)-3-tert-butylbenzene (16.2 g, 0.058 mol) in tert-butyl alcohol (50 mL) and the reaction mixture was allowed to stir at 0° C. for 12 h. The reaction mixture was quenched by the addition of sodium sulfite. The reaction mixture was diluted with water (500 mL) and ethyl acetate (500 mL). The aqueous phase was separated and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:2) gave 16.75 g (92%, 32% ee) of (±)-3-[2-(benzyloxy)-3-tert-butylphenyl]propane-1,2-diol as a white solid. mp 79-81° C.; Anal. calcd. for C20H26O3: C, 76.4; H, 8.33. Found: C, 76.39; H, 8.22.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([Cl:25])[C:22]([CH2:26]Br)=[C:21]([Cl:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:25][C:23]1[CH:24]=[CH:19][CH:20]=[C:21]([Cl:28])[C:22]=1[CH2:26][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2c(Cl)cccc2Cl)CCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-2,6-dichlorotoluene (1.19 g, 4.8 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL DMF was stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, saturated NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 900 mg (56%) of the 9-[(2,6-dichlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white foam. 1H NMR (CDCl3) δ 7.4-7.2 (m, 6H), 5.6 (s, 2H), 4.0 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.55 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1725 and 1652. MS (ES) m/e 400, 402, 404.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Cc1cc(N)n(C)n1
Product: Cc1ccc(Nc2cc(C)nn2C)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 5-Amino-1,3-dimethylpyrazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=326.3 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:21])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(COc2ccccc2)[nH]n1
Yield: 54.7 %

Procedure:
Hydrazine hydrate (0.197 mL, 4.06 mmol) was added to a stirring room temperature solution of 40 (1.0163 g, 4.06 mmol) in EtOH (4.1 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 92:4:4 Hexanes:CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.5474 g (54.7%) of 41. 1H (CDCl3, 400 MHz): δ 12.12 (1H, broad s), 7.28 (2H, t, J=7.8 Hz), 7.01-6.94 (3H, m), 6.91 (1H, s), 5.17 (2H, s), 4.36 (2H, q, J=7.0 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 158.11, 129.48, 121.26, 114.71, 107.83, 62.61, 61.31, 14.17 ppm. HPLC: 9.505 min.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([O:35][CH3:36])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([CH:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)[N:19]=2)=[CH:22][C:23]=1[O:35][CH3:36]
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 7 mL) was added to a solution of tert-butyl N-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate (240 mg, 0.529 mmol) in dichloromethane (4 mL) at 0° C. 15 minutes later, the ice-bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The solvents were evaporated and the residue was dissolved in dichloromethane. Sodium hydroxide (1.0N) was added to adjust the pH to about 10. The layers were separated and the aqueous layer was extracted with dichloromethane four times. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (178 mg, 95%). HPLC (Waters 486-Column: delta pak, C18, 5 um, 300 Å, 150×3.9 mm. Eluents: 5% B/A to 95% B/A in 10 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 1.0 mL/min.) Rt=6.45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=1[NH2:24]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:24][C:23]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:22]=2[F:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1cc(F)ccc1F
Product: O=C(Nc1cc(F)ccc1F)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2,5-difluoroaniline (50 mg, 0.39 mmol). The title compound was obtained as a solid (45 mg, 44% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.62 (1H, m), 9.00 (2H, s), 8.75 (1H, s), 7.50 (1H, m), 7.48 (1H, m), 7.40 (1H, m). MS m/z: 460.05, 462.04 [M+H]+.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH3:24])[C:22]([CH:25]([CH3:27])[CH3:26])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>S(Cl)(Cl)=O.CO>[CH3:24][N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([S:2](=[O:5])(=[O:3])[NH:31][CH:28]4[CH2:30][CH2:29]4)=[CH:9][CH:8]=3)[N:18]=2)=[CH:20][N:21]=[C:22]1[CH:25]([CH3:27])[CH3:26]
Reactant: NC1CC1
Reactant: CC(C)c1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CC(C)c1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC4CC4)cc3)n2)n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solution of 2-anilino-4-(1-methyl-2-isopropylimidazol-5-yl)pyrimidine (Method 71; 158 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled at 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of cyclopropylamine (570 μl, 8.1 mmol) in MeOH (3 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. Trituration with water results in a solid which was washed water (3×20 ml) collected by filtration and dried under vacuum at 60° C. to yield the title compound (205 mg, 92%) as a solid. NMR: 0.30 (m, 2H), 0.45 (m, 2H), 1.24 (d, 6H), 2.19 (m, 1H), 3.17 (m, 1H), 4.01 (s, 3H), 7.19 (d, 1H), 7.70 (d, 2H), 7.92 (d, 2H), 8.02 (m, 1H), 8.50 (d, 1H), 9.90 (brs, 1H); m/z 413.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:3]1.B.[OH:18]O>>[OH:18][CH2:1][CH:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:3]1
Reactant: OO
Reactant: C=C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: B
Product: CC(C)(C)OC(=O)N1CC2CC(CO)CC2C1

Procedure:
Methods for the synthesis of suitable 3-azabicyclo[3.3.0]octane intermediates vary. For instance, Flynn et al., Tetrahedron 53(1): 1-20 (1996), provides two approaches to suitably functionalized 3-azabicyclo[3.3.0]octanes. Such reference is herein incorporated by reference with regard to such synthetic teaching. The first approach involves the palladium-catalyzed [3+2] cycloaddition reaction of 2-trimethylsilylmethyl-2-propen-1-yl acetate with dimethyl maleate. The resulting diester is saponified, treated with acetic anhydride, and pyrolyzed to give the fused cyclic anhydride, tetrahydro-5-methylene-1H-cyclopenta[c]furan-1,3(3aH)-dione. Treatment with ammonia followed by cyclization with acetyl chloride gives the imide, tetrahydro-5-methylene-1H-cyclopenta[c]pyrrole-1,3(2H,2aH)-dione. Reduction with lithium aluminum hydride and protection of the free amine with di-tert-butyl dicarbonate gives 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane. Subsequent transformations, using this methylene compound, are possible. For instance, ozonolysis of 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane will give 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-one. Alternately, treatment of 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane with borane, followed by aqueous basic hydrogen peroxide, will produce 7-(hydroxymethyl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane. Oxidation of this alcohol by any number of methods, known to those of skill in the art of organic synthesis, will generate 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid, a key intermediate for the synthesis of compounds of the present invention.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:2]=[CH2:3]
Reactant: CCC(=O)NCCc1c[nH]c2ccc(O)cc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2[nH]cc(CCNC(=O)CC)c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Allyl bromide (11 g, 90.8 mmol.) was added, under argon atmosphere, to a mixture of N-[2-(5-hydroxyindol-3-yl)ethyl]propionamide (20.0 g, 92.5 mmol.), cesium carbonate (31.6 g, 97 mmol.) and N,N-dimethylformamide (150 mL) at 0° C. The reaction mixture was stirred for one hour at 50° C., to which was added water. The product was extracted with ethyl acetate. The extract solution was washed with water and dried. The solvent was then distilled off to leave the title compound (yield 20.0 g, 79.4%) as an oily product. This product was used, without further purification, for the subsequent reaction.
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.[N+:13]([CH3:16])([O-:15])=[O:14].C(O)(=O)C>CO>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:3]([OH:12])[CH2:16][N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(C(O)C[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
An aqueous sodium hydroxide solution (1.5 g of sodium hydroxide (37 mmol) was dissolved in 15 ml of water) was added dropwise to a solution of m-anisaldehyde (5.0 g, 37 mmol) and nitromethane (4.0 ml, 73 mmol) in methanol (50 ml) keeping the temperature of the solution at not higher than 30° C. The reaction mixture was then stirred at room temperature for 4 hours. Upon cooling on ice, an aqueous acetic acid solution (glacial acetic acid (37 mmol) was dissolved in 250 ml of water) was added, the resulting reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and a 5% aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (6.09 g).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([C:11]2([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:19].C(N(CC)CC)C.[C:40]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([C:11]2([NH:17][C:18]([N:51]3[CH2:52][CH2:53][N:48]([C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:49][CH2:50]3)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of 114 mg (0.9 mmol) of N,N-dimethylaminopyridine and 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in methylene chloride was added to a solution of 2.03 g (9.3 mmol) of di-t-butyl dicarbonate in 60 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Thereafter, a solution of 1.88 g (18.6 mmol) of triethylamine and 1.86 g (9.8 mmol) of 1-(benzoyl)piperazine in methylene chloride was added thereto, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diethyl ether to obtain 3.60 g (86%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:8][C:5]1[N:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(N2CCC(CCO)CC2)nn1
Temperature: 150 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 19.3 parts of 3-chloro-6-methylpyridazine, 19.4 parts of 4-piperidineethanol, 16 parts of sodium carbonate and 0.9 parts of N,N-dimethylacetamide was stirred for 5 hours at about 150° C. After cooling, the reaction mixture was diluted with water and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated, yielding 31.5 parts (95%) of 1-(6-methyl-3-pyridazinyl)-4-piperidineethanol (int. 83).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[N:20][N:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:24]=4)[CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:40][CH2:41][CH2:42][OH:43])=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[N:20][N:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[O:30])=[CH:27][CH:28]=4)[CH:22]=3)=[N:9]2)=[CH:37][CH:38]=1
Reactant: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(O)ccc32)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(OCCCO)ccc32)cc1
Yield: 63 %

Procedure:
A solution of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-ol (60 mg; 0.12 mmol; 1.0 eq.), 3-bromo-1-propanol (24 mg; 0.18 mmol; 1.5 eq.) and cesium carbonate (77 mg; 0.24 mmol; 2.0 eq.) in DMF (1.2 mL) was stirred at RT O/N. The reaction mixture was then diluted with DCM and washed with brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude by preparative HPLC gave the title compound as a white powder (43 mg, 64%).
Reaction SMILES: [C:1]([CH:3]([CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl[CH:18]([CH2:24][CH2:25][Cl:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(C(C(C1C=CC=CC=1)C)C(OC)=O)#N.BrC(CCBr)C(OC)=O>>[C:11]1([CH:9]([C:3]([C:1]#[N:2])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:24][CH2:25][Cl:26])[CH3:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(Cl)CCCl
Reactant: CCOC(=O)C(C#N)C(C)c1ccccc1
Agent: COC(=O)C(Br)CCBr
Agent: COC(=O)C(C#N)C(C)c1ccccc1
Product: CCOC(=O)C(CCCl)C(C#N)(C(=O)OCC)C(C)c1ccccc1

Procedure:
Ethyl 2-cyano-3-phenylbutyrate and ethyl 2,4-dichlorbutyrate can be used in place of methyl 2-cyano-3-phenylbutyrate and methyl 2,4-dibromobutyrate, respectively, in the alkylation reaction of Example 3 to produce the corresponding diethyl 2-phenyl-3-cyano-6-chlorohexane-3,4-dicarboxylate. The latter product can then be reacted with the tricarboxylate of Example 4 and the dicarboxylate of Example 7 to give the corresponding pentaester and tetraester products.
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.ClCCCl.[C:20](Cl)(=[O:22])[CH3:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[C:20]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: O=C1Nc2ccccc2Oc2sccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (5 g) was suspended to 1,2-dichloroethane (50 ml) and acetyl chloride was added (2.2 g). To this reaction system was added portionwise aluminum chloride (15 g) under ice-cooling and the mixture was stirred at room temperature for 10 minutes. The reaction system was poured into ice. Chloroform was added and the mixture was stirred for 15 minutes. The precipitated crystals were collected by filtration to give 2-acetylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (5.2 g).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[N:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]2[OH:26].CCOCC>N1C=CC=CC=1>[OH:26][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[CH:12]=2)[N:17]=[N:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)c1nnc2ccc(NS(C)(=O)=O)cc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulphonic anhydride (1.392 g.) was added to a solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (0.932 g.) in dry pyridine (20 ml.), and the mixture was stirred at room temperature overnight. The resulting solution was poured into ether (500 ml.) and the amorphous solid which precipitated was filtered off and applied to a silica column (100 g. Kieselgel 60). Elution with a mixture of 15% v/v ethanol and 85% v/v chloroform, and evaporation of the appropriate fractions gave ethyl 4-hydroxy-6-(methanesulphonylamino)cinnolin-3-yl carboxylate, m.p. 274°-5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C[CH2:12][N:13]=[C:14]=NCCCN(C)C.C(N(CC)C(C)C)(C)C.CN[N:33](NC)[SH:34](=[O:36])=[O:35]>ClCCCl.CN(C1C=CN=CC=1)C.O.Cl>[CH3:12][N:13]([CH3:14])[S:34]([NH:33][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:36])=[O:35]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: CNN(NC)[SH](=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
To a solution of 4-fluorobenzoic acid (700 mg, 5.0 mmol) in 1,2-dichloroethane (30 mL) was added EDCI (2.38 g, 12.5 mmol), DMAP (1.52 mg, 12.5 mmol) and N,N-diisopropylethylamine (2.17 mL, 12.5 mmol) and stirred for 20 minutes at room temperature. N,N-dimethylaminosulfonamide (1.24 g, 10.0 mmol) was added to the solution and the mixture heated at 60° C. for 2.5 hours. The mixture was cooled, diluted with water (20 mL) and 2M HCl (20 mL) and extracted with DCM (3×30 mL), washed with water (20 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the title compound as a white solid (585 mg, 47%). No further purification was necessary.