Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=C(C=CC=1O)C=CC(Cl)=O.S(Cl)(Cl)=O.[C@H:18]1([O:29][C@@H:30]2[C@@H:35]([CH2:36][OH:37])[O:34][C@@H:33](Br)[C@H:32]([OH:39])[C@H:31]2[OH:40])[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]1[OH:20].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O.CS(C)=O>[C@H:18]1([O:29][C@@H:30]2[C@@H:35]([CH2:36][OH:37])[O:34][C@@H:33]([N:41]=[N+:42]=[N-:43])[C@H:32]([OH:39])[C@H:31]2[OH:40])[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]1[OH:20]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Br)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: O=C(Cl)C=Cc1ccc(O)c(O)c1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
A method for producing compounds of the formula: ##STR8## wherein A is selected from the group consisting of alkali metal cations and alkaline earth metal cations which comprises reacting 3,4-dihydroxycinnamic acid with acetic anhydride in pyridine for 18-30 hours, in organic solvents, giving 3,4-dihydroxycinnamic acid, diacetate, then converting to 3,4-dihydroxycinnamic acid chloride by treating with thionyl chloride in dimethylformamide at -20° to -18° C. for 30-90 minutes; reacting 4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes, extracting in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate, then catalytically reducing, giving 4-Oα-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester); reacting a solution of the 3,4-dihydroxycinnamic acid chloride in dimethylformamide at -20° to -15° C. with a solution of the 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate in pyridine at -15° to -5° C. for 20-40 minutes, then at -5° to 20° C. for 1-2 hours followed by extracting with organic solvents, giving N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide, nonaacetate (nonaester), then converting to N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide by reacting in a mixture of methanol, triethylamine and water, under an inert atmosphere for 20-30 hours followed by heating at reflux for 2-6 hours and extracting in organic solvents, reacting this derivative with triethylamine sulfur trioxide in N,N-dimethylacetamide under an inert atmosphere at 50°-70° C. for 15-20 hours, and then treating with an alkali metal or alkaline earth metal acetate in water.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Yield: 95 %

Procedure:
Thus, for example, a process for the nitration of anthraquinone in sulphuric acid by means of nitric acid is known from German Offenlegungsschrift (German Published Specification) 2,039,822. Even using the best embodiment of this process, the crude product must be purified by washing with acid amides, for example dimethylformamide. 95-96% pure 1-nitroanthraquinone is obtained in 42% yield. A disadvantage of this process is that organic solvents are used, the recovery of which, in special apparatuses, is difficult and expensive, solvent losses being unavoidable.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2c(Cl)cccc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(Cl)cccc5s4)cc3CC[C@@H]12
Yield: 49 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,4-dichlorobenzo-thiazole (94 mg, 0.46 mmol/and 1 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 80 mg (49%) of the title compound as an amorphous solid. mp 207°-209°. FDMS: m/e=429 α[D]589 =+63.86 (c=0.57, chloroform).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([CH:24]([F:26])[F:25])=[N:11][CH:12]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[C:29]2[N:30]([CH:35]=[CH:36][C:37]=2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:31](Cl)=[N:32][N:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1>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]>[C:1]([NH:5][S:6]([C:9]1[C:10]([CH:24]([F:25])[F:26])=[N:11][CH:12]=[C:13]([C:31]2[N:30]3[CH:35]=[CH:36][C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[C:29]3[C:28]([Cl:27])=[N:33][N:32]=2)[CH:14]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1nnc(Cl)n2ccc(-c3ccccc3)c12
Reactant: CC(C)(C)NS(=O)(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1C(F)F
Agent: [Pd]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)cnc1C(F)F
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 35.2 %

Procedure:
To a solution of N-(tert-butyl)-2-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.118 g, 0.303 mmol) and 1,4-dichloro-8-phenylpyrrolo[1,2-d][1,2,4]triazine (0.080 g, 0.30 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL) was added K3PO4 (0.129 g, 0.606 mmol) and the reaction mixture was purged with nitrogen for 10 minutes. Tricyclohexylphosphonium tetrafluoroborate (0.011 g, 0.030 mmol) was added followed by Pd2(dba)3 (0.014 g, 0.015 mmol) and the nitrogen purging was continued for further 5 minutes. The reaction mixture was heated at 100° C. for 4 h then allowed to cool to ambient temperature. The reaction mixture was filtered through CELITE® and the filter cake was washed with EtOAc (2×50 mL). The filtrate was washed with water (50 mL). The organic phase was separated and the aqueous phase was further extracted with EtOAc (50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash Isco (REDISEP®, SiO2, 40 g, 0-50% EtOAc/petroleum ether) to obtain N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)-2-(difluoromethyl)pyridine-3-sulfonamide (0.052 g, 35%) as a pale yellow solid. LCMS Method B-12: retention time 2.24 min, [M+1]=492.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.19 (s, 9H), 7.25 (d, J=2.8 Hz, 1H), 7.41-7.54 (m, 5H), 7.73 (t, J=52.4 Hz, 1H), 7.99 (d, J=2.8 Hz, 1H), 8.37 (s, 1H), 8.90 (br s, 1H), 9.45 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH:11](OC)[O:12]C)[CH:5]=1>CCO.C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH:11]=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(C(OC)OC)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(N)c(C=O)c1
Reaction time: 0.08 h

Procedure:
Compound 6 (0.95 g, 4.2 mmol) was dissolved at room temperature in 15 mL of a solvent mixture composed of EtOH-acetic acid-water 2:2:1. The strongly colored yellow solution became pale yellow in 5 minutes. The mixture was let stand for an additional 15 minutes before it was evaporated to dryness and further dried in high vacuum overnight to get Compound 7 as a yellow powder.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[C@@H:8]([NH:12][C:13]1[N:18]=[C:17]2[CH2:19][NH:20][CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1)([CH2:10][CH3:11])[CH3:9].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C@@H:8]([NH:12][C:13]1[N:18]=[C:17]2[CH2:19][N:20]([C:2](=[O:1])[CH3:4])[CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1)([CH2:10][CH3:11])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(C)=O)C2
Reaction time: 1 h

Procedure:
A solution of (S)—N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (169.0 mg) in DCM (3.18 mL) at 0° C. was treated with pyridine (0.077 mL, 0.954 mmol), followed by acetic anhydride (0.060 mL, 0.636 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH, filtered through a Millipore® 0.45 μm syringe filter, and purified by HPLC Method A to give the title compound, as a TFA salt, as a yellow semisolid (84.9 mg, 43.4% over two steps). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 0.98 (m, 3H), 1.27 (m, 3H), 1.68 (m, 2H), 1.97 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.74 (td, J=5.9, 1.5 Hz, 0.7H), 2.84 (td, J=5.9, 1.5 Hz, 1.3H), 3.11 (m, 2H), 3.45 (m, 2H), 3.82 (t, J=5.9 Hz, 1.3H), 3.86 (m, 0.7H), 3.97 (m, 1H), 4.50 (m, 1H), 4.61 (d, J=3.9 Hz, 0.7H), 4.64 (s, 1.3H), 6.87 (m, 1H), 6.97 (ddd, J=11.3, 8.7, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 460.00.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][N:13]=3)[NH:9][C:8]=2[CH:21]=1)(=[NH:3])[NH2:2].C1C=CC2N(O)N=NC=2C=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH2:72]([NH2:79])[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>C(#N)C.CCOCC.CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10]([C:12]3[N:13]=[CH:14][CH:15]=[C:16]([C:18]([NH:79][CH2:72][C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)=[O:20])[CH:17]=3)=[N:9][C:8]=2[CH:21]=1)(=[NH:3])[NH2:2]
Reactant: NCc1ccccc1
Reactant: N=C(N)c1ccc2nc(-c3cc(C(=O)O)ccn3)[nH]c2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)NCc4ccccc4)ccn3)nc2c1
Reaction time: 12 h
Yield: 33.3 %

Procedure:
A mixture comprising 2-(6-amidino-1H-benzimidazol-2-yl)pyridine-4-carboxylic acid (0.02 g, 0.06 mmol), HOBT (0.008 g, 0.07 mmol), PyBOP (0.032 g, 0.07 mmol), DMF (0.5 mL) and N-methylmorpholine (0.013 mL, 0.12 mmol) was shaken for 10 minutes and then benzyl amine (13 μL, 0.12 mmol) was added. The mixture was shaken for approximately 12 hours and combined with a mixture comprising ether and acetonitrile (5 mL) to give a precipitate. The precipitate was isolated by filtration and purified by HPLC to provide 6-(5-amidino-1H-benzimidazol-2-yl)-N-benzylpyridine-4-carboxamide (10 mg, 0.02 mmol); 1H-NMR (300 Mhz, DMSO-d6): 4.5 (d, 2H, J=5.5 Hz), 7.3 (m, 5H), 7.7 (m, 2H), 8.0 (dd, 1H), 8.2 (bs, 1H), 8.8 (s, 1H), 8.9 (m, 3H), 9.3 (s, 2H), 9.6 (t, 1H, J=1.5 Hz); MS (ESI), Calculated for C21H18N6O: 370.4, Found (MH+): 371.1.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:13]([O:15][C:16](=[O:25])[CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH3:14].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.C(O)C(N)(CO)CO.Cl>CC(O)C>[CH2:13]([O:15][C:16](=[O:25])[CH2:17][CH:18]([OH:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH3:14]
Reactant: CCOC(=O)CC(=O)c1cccs1
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: CC(C)O
Product: CCOC(=O)CC(O)c1cccs1
Reaction time: 24 h

Procedure:
An aqueous solution comprising a composition of 2% glucose, 1% yeast extract, 1% polypeptone, and 0.6% malt extract was used as the medium, and Filobasidium uniguttulatum IFO 0699 was inoculated into this and aerobically cultured at 28° C. for 24 hours. After completion of the culturing, the culture medium (1 ml) was collected and centrifuged to isolate the cells. 3-Oxo-3-(2-thienyl)propionic acid ethyl ester to be used as the substrate was synthesized in accordance with the method described in EP-A-751427. Said cells were suspended in 200 μl of a reaction solution comprising 100 mM glucose, 0.24% 3-oxo-3-(2-thienyl)propionic acid ethyl ester, 0.01% NADH, 0.01% NADPH and 100 mM Tris-HCl buffer (pH 7.5) and allowed to undergo the reaction at 30° C. on a shaker. After 18 hours of the commencement of the reaction, 800 μl of 2-propanol was added thereto, the cells were removed by centrifugation, and then a sample of the supernatant was analyzed by HPLC. The analysis was carried out under the following conditions using Chiralpak AD-RH (mfd. by Daicel) as the HPLC column.
Reaction SMILES: C(OC[C:6]1[O:7][C:8]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:9]=2[CH:10]=1)(=O)C.C(=O)([O-])[O-:18].[K+].[K+].C(OCC)(=O)C>CO>[F:16][C:11]1[C:9]2[CH:10]=[C:6]([OH:18])[O:7][C:8]=2[C:14]([F:15])=[CH:13][CH:12]=1
Reactant: CC(=O)OCc1cc2c(F)ccc(F)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1cc2c(F)ccc(F)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
2-Acetoxymethyl-4,7-difluorobenzofuran (252 mg) was dissolved in 5 ml methanol, 455 mg potassium carbonate was added thereto at room temperature, and the mixture was stirred for 2 hours at the same temperature. Ethyl acetate was added to the reaction solution, and the organic layer was washed with brine. It was dried over anhydrous magnesium sulfate and then evaporated, and the resulting residue was subjected to silica gel chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 161 mg 4,7-difluoro-2-hydroxybenzofuran as a colorless oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:3]=1.B(F)(F)F.CCOCC.N(OCCC(C)C)=O.[I:33]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CC#N>[I:33][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(N)cc12
Reactant: II
Agent: CC(C)CCON=O
Agent: FB(F)F
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnn2ccc(I)cc12
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A 2 L round bottom flask was charged with ethyl 5-aminopyrazolo[1,5-a]pyridine-3-carboxylate (I-40) (28.8 g, 140 mmol) and CH3CN (450 mL). The suspension was cooled to 10° C. and BF3.Et2O (26.3 mL, 29.7 g, 209 mmol) was added in one portion. The resulting light slurry was cooled to −15° C. and isopentyl nitrite (28 mL, 24.5 g, 209 mmol) was added at −15 to −10° C. over 5 minutes. The mixture was then warmed to 0° C. and stirred at 0-5° C. over 2 hours and a dark suspension was obtained. Iodine (2.7 g, 11 mmol) and KI (35.1 g, 166 mmol) were added at 0 to 5° C. in portions over 2 minutes. A dark mixture was obtained with gas evolution. The mixture was warmed to 20° C. and stirred at 20° C. over 4 hours. A sample was taken for analysis and HPLC showed consumption of the diazonium intermediate. A solution of sodium thiosulfate pentahydrate (75 g, 302 mmol) in water (450 mL) was added and the mixture was stirred at 20° C. over 5 hours. The mixture was cooled to 0-5° C. and stirred at 0-5° C. over 30 minutes. The slurry was filtered and the solid cake was rinsed with CH3CN/H2O (1:1, 400 mL) and water (400 mL). The solid was air dried over 72 hours to give ethyl 5-iodopyrazolo[1,5-a]pyridine-3-carboxylate (I-41) as a red solid. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, 1 H), 8.41 (d, 1 H), 8.40 (s, 1 H), 7.39 (dd, 1 H), 4.31 (q, 2 H), 1.34 (t, 3 H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10]([CH2:19]Br)=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=O.Cl.[C:22]([O:26][C:27](=[O:35])[C@H:28]([CH2:30][CH2:31][C:32](=[O:34])[NH2:33])[NH2:29])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:11]2[C:10]=1[CH2:19][N:29]([CH:28]([CH2:30][CH2:31][C:32](=[O:34])[NH2:33])[C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:35])[C:12]2=[O:14]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Reactant: COC(=O)c1cccc(Br)c1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCC(N)=O)N1Cc2c(Br)cccc2C1=O
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Triethylamine (4.66 g, 46.09 mmol) was added to a stirred suspension of methyl 3-bromo-2-bromomethylbenzoate (6.45 g, 20.95 mmol) and L-glutamine t-butyl ester hydrochloride (5.0 g, 20.95 mmol) in THF (100 mL). The mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and solvent was removed. The residue was dissolved in methylene chloride (100 mL) and washed with water (2×80 mL), brine (80 mL) and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (CH2Cl2:CH3OH 97.5:2.5) to afford tert-butyl 2-(4-bromo-1-oxoisoindolin-2-yl)-4-carbamoylbutanoate (3.97 g, 48%): 1H NMR (CDCl3) δ 7.74 (d, J=7.1 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 6.15 (s, 1H), 5.77 (s, 1H), 5.02-4.96 (m, 1H), 4.58 (d, J=17.4 Hz, 1H), 4.34 (d, J=17.4 Hz, 1H), 2.45-2.10 (m, 4H), 1.46 (s, 9H); 13C NMR (CDCl3) δ 173.83, 169.42, 168.74, 142.28, 134.70, 133.65, 129.80, 122.70, 117.75, 82.66, 54.29, 47.80, 32.27, 27.95, 25.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:15]2[CH:14]=[C:13](B(O)O)[CH:12]=[CH:11][C:10]=2[C:9]2[N:19]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[CH:21][C:8]=2[C:7]1=[O:28].FC1C=C(C2C(OC)=NC(C)=CC=2C)C=CC=1C1N(C2CCOCC2)N=CC=1C(OCC)=O.Br[C:69]1[C:70]([O:76][CH2:77][CH3:78])=[N:71][CH:72]=[CH:73][C:74]=1[CH3:75].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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.O>[CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:15]2[CH:14]=[C:13]([C:69]3[C:70]([O:76][CH2:77][CH3:78])=[N:71][CH:72]=[CH:73][C:74]=3[CH3:75])[CH:12]=[CH:11][C:10]=2[C:9]2[N:19]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[CH:21][C:8]=2[C:7]1=[O:28]
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(B(O)O)cc32)c(OC)c1
Reactant: CCOc1nccc(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)c1cnn(C2CCOCC2)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1F
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1nccc(C)c1-c1ccc2c3c(cnn3C3CCOCC3)c(=O)n(Cc3ccc(OC)cc3OC)c2c1

Procedure:
[5-(2,4-dimethoxybenzyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl]boronic acid obtained in Preparation Example 1 (70 mg) was dissolved in 1,4-dioxane (4 mL). 3-bromo-2-ethoxy-4-methylpyridine obtained in Preparation Example 44 (49 mg), Pd(PPh3)4 (8.7 mg), cesium carbonate (148 mg) and water (1 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 130° C. for two hours. The reaction mixture was returned to room temperature and then partitioned by adding ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 50% to 80%) to give 5-(2,4-dimethoxybenzyl)-7-(2-ethoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (55 mg). The 5-(2,4-dimethoxybenzyl)-7-(2-ethoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (55 mg) was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70% to 80% to 100%) to give the title compound (17 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:17][CH2:16]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.3 %

Procedure:
3-(chlorosulfonyl)benzoic acid (200 mg, 0.906 mmol) was added to the 1-methylpiperazine (100 mg, 0.997 mmol) in presence of potassium carbonate (251 mg, 1.813 mmol) in THF (Volume: 5 ml) at room temperature and the reaction mixture was stirred for 12 h at room temperature. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography (3% CH3OH/CH2Cl2) afforded the product 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid (100 mg, 0.320 mmol, 35.3% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.77 (m, 2H), 7.63-7.55 (m, 2H), 3.04 (m, 4H), 2.46 (m 4H), 2.31 (s, 3H). Mass [M+H]+:285.1
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][C:14]([OH:17])([CH3:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:16][C:14]1([OH:17])[CH2:15][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC1(O)CN(C2CN(C(=O)OC(C)(C)C)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-hydroxy-3-methyl-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.09 g, 0.37 mmol) in DCM/TFA (2 mL/2 mL). The reaction mixture was stirred for 90 min at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3-Methyl-[1,3′]biazetidinyl-3-ol as a colourless oil (0.04 g, 76%). 1H NMR (300 MHz, CDCl3): δ 3.68-3.51 (m, 6 H), 3.25 (d, J=7.6 Hz, 2 H), 3.15 (d, J=7.6 Hz, 2 H), 1.49 (s, 3 H).