Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:28]=1)[CH3:2].C(OO)(=[O:36])C.C(O)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:12][C:11]=3[N+:10]([O-:36])=[CH:9][C:8]=2[N:28]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Reactant: CC(=O)OO
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCc1nc2c[n+]([O-])c3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (2.9 g, 6.32 mmol) was dissolved in ethyl acetate (25 mL). 32% Peracetic acid in acetic acid (1.99 mL, 9.48 mmol) was added to the solution and the mixture was heated to 50° C. for 2 hours. Another 0.5 mL of the peracetic acid solution (2.37 mmol) was added and the reaction was stirred for 1 hour. A solution of sodium metabisulfite in water (1.5 g in 3.0 mL) was added in two portions and the reaction mixture was stirred for 10 minutes. The heat was then removed and the solution was brought to pH≈10 with saturated aqueous sodium carbonate (˜15 mL). The resulting precipitate was filtered, washed with ethyl acetate (10 mL) and water (10 mL), and dried under vacuum to afford 2.8 g of tert-butyl 2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as a white paper-like solid with some water remaining.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([OH:18])[CH2:7][C@@H:8]2[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([O:18][C@H:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C@@H:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:7]1)[CH:22]=[CH2:21]
Reactant: O=C(N[C@H]1C[C@@H](O)c2ccc(Br)cc21)C(F)(F)F
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1C[C@H](NC(=O)C(F)(F)F)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
Step Z (5). A solution of 1.7 g (5.25 mmol) of N-((1S,3R)-6-bromo-3-hydroxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide from step Z (4) was dissolved in 30 mL of DMF, and a suspension of 60% NaH in mineral oil (630 mg, 15.75 mmol) was added in portions to minimize gas evolution. The resulting reaction mixture was stirred at rt for 10 min, and then allyl bromide (953 mg, 7.8 mmol) was added. After stirring at rt for 3 h, the starting material was consumed. The reaction solution was diluted with 60 mL of ether and the remaining NaH was slowly quenched with water. Brine (20 mL) was then added, and the organic layer was removed followed by extraction of the aqueous layer with 2 more portions of ether. The combined organics were dried and concentrated, and the crude product was purified by chromatography eluting with a gradient of 0 to 15% EtOAc in hexanes to provide 1.26 g (74% yield) of N-((1S,3R)-3-(allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide. 1H NMR (500 MHz, CDCl3) δ ppm 2.06 (ddd, J=13.89, 3.05, 2.90 Hz, 1H) 2.70 (ddd, J=13.89, 7.17, 5.49 Hz, 1H) 4.07 (ddd, J=5.65, 1.53, 1.37 Hz, 2H) 4.80 (dd, J=5.65, 2.59 Hz, 1H) 5.22 (dd, J=10.38, 1.22 Hz, 1H) 5.29 (ddd, J=17.32, 3.13, 1.53 Hz, 1H) 5.37-5.44 (m, 1H) 5.84-5.95 (m, 1H) 6.81 (d, J=7.63 Hz, 1H) 7.30 (d, J=7.93 Hz, 1H) 7.49 (dd, J=7.93, 1.83 Hz, 1H) 7.58 (d, J=1.53 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[C:9]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.CN(C)[CH2:28][CH2:29][CH2:30]N=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[O:14])=[C:9]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:28]1[CH2:29][CH2:30][CH2:2][C:10](=[O:11])[CH:9]=1)=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCN(CC)C(=O)COc1c(S(=O)(=O)CC)ccc(C(=O)O)c1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)COc1c(S(=O)(=O)CC)ccc(C(=O)OC2=CC(=O)CCC2)c1Cl

Procedure:
0.500 g (1.30 mmol) of 2-chloro-3-(N,N-diethylaminocarbonylmethoxy)-4-ethylsulfonylbenzoic acid, 0.163 g (1.30 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide-hydrochloride and 0.002 g of DMAP were stirred for 10 hours at RT in 15 ml of CH2Cl2. The mixture was subsequently diluted with CH2Cl2 and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. After the organic phases had been dried over Na2SO4 and concentrated completely, the product was obtained in the form of a brown resin.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:19][C:6]2([C:15]3[C:9]4[C:10](=[CH:16][NH:17][CH2:18][C:8]=4[CH2:7]2)[CH:11]=[CH:12][O:13][CH:14]=3)[O:5][CH2:4]1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(Cl)(Cl)Cl.CCCCCC>[CH2:4]1[O:5][C:6]2([C:15]3[C:9]4[C:10](=[CH:16][N:17]([S:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)(=[O:28])=[O:27])[CH2:18][C:8]=4[CH2:7]2)[CH:11]=[CH:12][O:13][CH:14]=3)[O:19][CH2:3]1
Reactant: C1=CC2=CNCC3=C2C(=CO1)C1(C3)OCCO1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)N1C=C2C=COC=C3C2=C(C1)CC31OCCO1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
60% Sodium hydride 33 mg was added to a solution of compound (33) in dry dimethylformamide 2 ml with cooling in ice and the mixture was stirred for 10 min. Then, benzenesulfonyl chloride 152 mg was added. The mixture was heated at 60° C. for 14 h. Ice-water was added to the reaction mixtures, which was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was choromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound (34) as a pale yellow oil, 187 mg. Yield 69%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.B(O)O>>[N:6]1[CH:7]=[CH:8][CH:3]=[C:4]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][NH:6][CH2:7]3)[CH:5]=1
Reactant: Brc1cccc2c1CCNC2
Agent: OBO
Product: c1cncc(-c2cccc3c2CCNC3)c1

Procedure:
In close analogy to the procedure described above, 5-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[OH-:15].[Na+].Cl>C1COCC1>[OH:15][C:7]1[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]=1
Reactant: [OH-]
Reactant: COC(=O)c1cc(C(=O)O)nc(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(=O)O)nc(O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a stirred solution of 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester (120 mg, 0.55 mmol) in THF (3 mL) is added 1N NaOH (1.10 mL) and the mixture is stirred at room temperature for 18 hours. The solution is carefully acidified with 1N HCl and the solvent is removed under reduced pressure to give 2-hydroxypyrimidine-4,6-dicarboxylic acid. This is used as is in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[CH3:15]O>>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([O:11][CH3:12])[C:3]([OH:13])=[C:2]([Cl:1])[CH:10]=1
Reactant: CO
Reactant: COc1cc(C(=O)O)cc(Cl)c1O
Agent: Cl
Product: COC(=O)c1cc(Cl)c(O)c(OC)c1

Procedure:
A mixture of 5-chlorovanillic acid (5.0 g, 24.6 mmol) and conc. HCl (5 ml) in MeOH (100 ml) is heated at reflux for 48 hours. The solvent is removed in vacuo and water is added to the residue to yield a white precipitate, which is collected by filtration, washed with water, and then dissolved in Et2O. The solution is dried (Na2SO4) and the solvent removed in vacuo to yield 3-Chloro-4-hydroxy-5-methoxy-benzoic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH3:11])=[CH:5][CH2:6]OC(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:33]([N:35]([CH2:6][CH:5]=[C:4]([CH3:11])[CH:3]([O:2][CH3:1])[O:12][CH3:13])[CH2:36][CH3:37])[CH3:34]
Reactant: COC(OC)C(C)=CCOC(C)=O
Reactant: CCNCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN(CC)CC=C(C)C(OC)OC

Procedure:
A mixture of 56.4 g (0.30 mol) of 4-acetoxy-2-methyl-2-butenal dimethyl acetal, 150 ml of diethylamine, 675 mg (3 mmol) of palladium (II) acetate and 3.9 g (15 mmol) of triphenylphosphine was boiled under reflux for 15 hours under argon. AFter concentrating the mixture, the residue was suspended in 170 ml of ether/pentane (1:1), the solution was treated with active carbon, filtered over Hyflo and concentrated. The residual oil was firstly distilled at 40°-55°/0.3 mmHg over a 5 cm Vigreux column, there being obtained 57.1 g of N,N-diethyl-4,4-dimethoxy-3-methyl-2-butenylamine as a 90:10 (E/Z) mixture. This mixture was then fractionated over a 30 cm packed column. There were firstly obtained a total of 34.8 g (58%) of mixed fractions [(E/Z)=86:14] and then 14.5 g (24%) of pure (E)-N,N-diethyl-4,4-dimethoxy-3-methyl-2-butenylamine of boiling point 30°-32°/0.06 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[H-].[Na+].[Li+].CCC[CH2-].[CH3:16][N:17]1[C:21]([C:22](=[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)/[CH:23]=[CH:24]/[CH:25]=[O:26])=[N:20][N:19]=[N:18]1.Cl.[BH4-].[Na+]>C1COCC1>[C:34]1([C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([C:21]2[N:17]([CH3:16])[N:18]=[N:19][N:20]=2)/[CH:23]=[CH:24]/[CH:25]([OH:26])[CH2:7][CH:5]([OH:6])[CH2:4][C:3]([O:2][CH3:1])=[O:8])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cn1nnnc1C(/C=C/C=O)=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [CH2-]CCC
Solvent: C1CCOC1
Product: COC(=O)CC(O)CC(O)/C=C/C(=C(c1ccccc1)c1ccccc1)c1nnnn1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
Methylacetoacetate (0.525 mL; 4.87 mmole) was added to a suspension of sodium hydride (0.160 g; 80% disp. in mineral oil) in THF at 0° C. and stirred for 10 minutes. N-Butyllithium (2.14 mL; 2.5M solution in hexanes) was added and reaction stirred for 15 minutes. This solution was added to a solution of the aldehyde (1.0 g; 3.2 mmole) (prepared in Example 124) in THF at 0° C. and stirred for 30 minutes. The reaction was treated with 2N HCl (30 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried with MgSO4 and evaporated. The crude residue was triturated with hexane (3×25 mL) then dissolved in THF/CH3OH (4:1; 20 mL) and treated with triethylborane (3.2 mL; 1M solution in THF). Air was bubbled through the solution for 10 minutes and the reaction stirred for an additional 50 minutes. The solution was then cooled to -78° C. and treated with sodium borohydride (120 mg; 3.2 mmole) and stirred for 1 hour. The reaction was quenched with 2M HCl (100 mL) and extracted with EtOAc (3×20 mL). The organic layers were dried with MgSO4 and evaporated. The residue was dissolved in CH3OH (30 mL) and stirred for 15 hours. The solvent was evaporated and residue purified by chromatography using 50% EtOAc-hexane as eluent to afford the title compound as a yellow oil (470 mg; 33%). MS (CI): m/e=435 (M+H)+ ;
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([CH2:12][NH:13][C:14](=[O:17])[CH:15]=[CH2:16])[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>O>[C:19]1([N:25]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([CH2:12][NH:13][C:14](=[O:17])[CH:15]=[CH2:16])[C:9]([CH3:10])=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CC(=O)NCC(C(C)=O)C(=O)c1ccccc1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: C=CC(=O)NCc1c(C)nn(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 29.4 g of the 1-phenyl-2-(acrylamidomethyl)-butane-1,3-dione prepared according to Synthesis Example I, 12.9 g of phenylhydrazine, 180 ml of acetic acid and 180 ml of water was refluxed for 5 minutes, cooled to room temperature and then diluted with 600 ml of water. The crystals precipitated in this procedure were filtered off under suction and washed with diethyl ether. This gave 37.4 g of 1,5-diphenyl-3-methyl-4-acrylamidomethylpyrazole having a melting point of 157°-159° C. The 1H-NMR spectroscopic measurement confirmed the presence of this product:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(N(C(C)C)CC)(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=[N+]([O-])c1cccc(Oc2nc(Cl)nc3ccoc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
6.4 g (33.9 mmol) of 2,4-dichlorofuro[3,2-d]pyrimidine (see: International Publication Number WO 2008073785 and WO 2008152394) was dissolved in 32 mL of methanol, and 5.7 g (40.6 mmol) of 3-nitrophenol and 12 mL (67.7 mmol) of diisopropylethylamine were added thereto, and stirred for 24 hours at room temperature. Upon the completion of the reaction, the resulting solid was filtered and dried over under a reduced pressure to obtain 6.3 g of the title compound (yield: 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:15])[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([NH:15][C:11]1[S:12][C:13]([CH3:14])=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:22]
Reactant: COc1ccc(-c2nc(N)sc2C)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2C)cc1
Yield: 63.5 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-methyl-thiazol-2-ylamine prepared in Example 52 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1) to obtain a product as a white solid in a yield of 63.5%, mp: 174-175 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.51 (3H, s, ArCH3), 3.83 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.95 (3H, s, OCH3), 6.82˜6.92 (3H, m, ArH), 7.42˜7.56 (4H, m, ArH), 10.83 (1H, br, CONH); EI-MS m/e (%): 384.0 (M+, 66), 165.0 (100); HREI-MS Calcd. for C20H20N2O4S: 384.1144. found: 384.1143. Anal. Calcd. for C20H20N2O4S: C, 62.48; H, 5.24; N, 7.29. found: C, 62.30; H, 5.19; N, 7.30.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:16][C:17]1[CH:18]=[C:19]([N:24]2[C:29](=[O:30])[C:28](Cl)=[C:27]([Cl:32])[CH:26]=[N:25]2)[CH:20]=[CH:21][C:22]=1[F:23]>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([N:24]2[C:29](=[O:30])[C:28]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:27]([Cl:32])[CH:26]=[N:25]2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(F)c(F)c1
Reactant: CCCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1c(Cl)cnn(-c2ccc(F)c(F)c2)c1=O
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a stirred, room temperature solution of n-butanol (0.81 g, 10.93 mmol, 1.1 equiv.) in THF (20 mL) was slowly added 1.0 M sodium bis(trimethylsilyl)amide in THF (12 mL, 12 mmol, 1.2 equiv.). The reaction mixture was stirred for 0.5 hours, then it was transferred to a solution of 2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone (2.88 g, 10.4 mmol, 1.0 equiv.) in THF (80 mL). The resulting reaction mixture was stirred for 0.5 hours at room temperature to provide the title compound (2.5 g, 79.4%).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[CH:24][N:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[CH:24][N:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)N[C@H](C)C(=O)N3CC(C#N)C3)cn4COCC[Si](C)(C)C)ncn2c1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)N[C@H](C)C(=O)N5CC(C#N)C5)c4n3)ncn2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
In a round-bottomed flask, 2-(6-methyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (92 mg, 0.165 mmol) was dissolved in dichloromethane (0.8 ml) and trifluoroacetic acid (0.5 ml, 6.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.8 ml) and ethylenediamine (0.67 ml, 9.9 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 48 mg (65%) of 2-(6-methyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow powder. MS: (M+H)+=429; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.40 (br. s, 1H), 9.11 (s, 1H), 8.39-8.61 (m, 3H), 8.34 (d, J=7.2 Hz, 1H), 8.28 (s, 1H), 6.79-7.05 (m, 1H), 4.41-4.86 (m, 3H), 4.15-4.33 (m, 1H), 3.99-4.15 (m, 1H), 3.71-3.94 (m, 1H), 2.26 (s, 3H), 1.40 (d, J=4.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]1>ClCCl.CO>[Cl:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH2:12]1
Reactant: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2Cl)CC1
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(CCOc2ccc(N)cc2Cl)CC1

Procedure:
Prepared analogously to Example 3.1.b. from 1-[2-(2-chloro-4-nitrophenoxy)ethyl]4-methylpiperidine. Yield: 3.66 g (59% of theory); C14H21ClN2O (M=268.78); calc.: molecular ion peak (M+H)+: 269/271; found: molecular ion peak (M+H)+: 269/271; Rf value: 0.52 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]([N:29](C)[C:30](=O)C)([CH2:16][CH2:17][CH2:18][CH2:19][B:20]1[O:24]C(C)(C)C(C)(C)[O:21]1)[C:11]([O:13]CC)=[O:12]>Cl>[ClH:1].[ClH:1].[B:20]([CH2:19][CH2:18][CH2:17][CH2:16][C:10]([CH2:9][CH2:8][CH2:7][NH:6][CH2:5][C:4]1[CH:34]=[CH:35][C:36]([Cl:37])=[C:2]([Cl:1])[CH:3]=1)([NH:29][CH3:30])[C:11]([OH:13])=[O:12])([OH:24])[OH:21]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCNCc1ccc(Cl)c(Cl)c1)N(C)C(C)=O
Agent: Cl
Product: CNC(CCCCB(O)O)(CCCNCc1ccc(Cl)c(Cl)c1)C(=O)O
Yield: 87.4 %

Procedure:
A solution of ethyl 2-(3-(3,4-dichlorobenzylamino)propyl)-2-(N-methylacetamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (76 mg) in aq 6 M HCl was heated to reflux for 16 h, concentrated to dryness and purified by preparative HPLC. The resulting residue was redissolved in 2 N HCl and evaporated to give 6-borono-2-(3-(3,4-dichlorobenzylamino)propyl)-2-(methylamino)hexanoic acid dihydrochloride (19 mg, 12%-3 steps). 1H NMR (D2O, 500 MHz) δ 7.55 (bs, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 4.12 (s, 2H), 3.02 (t, J=7.2 Hz, 2H), 2.55 (s, 3H), 1.91-1.68 (m, 5H), 1.60-1.49 (m, 1H), 1.38-1.29 (m, 2H), 1.28-1.19 (m, 1H), 1.14-1.04 (m, 1H), 0.70 (t, J=7.2 Hz, 2H). ESI MS found for C17H27BCl2N2O4 m/z [405.4/407.4 (M+1)].
Reaction SMILES: [S-]C#N.[NH4+].C(Cl)(=O)C1C=CC=CC=1.[C:14]([N:22]=[C:23]=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:25]([C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[O:25]([C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH:34][C:23]([NH:22][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[S:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ccccc1Oc1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of ammonium thiocyanate (30.2 g) in anhydrous acetone (660 ml) was added dropwise benzoyl chloride (47.6 g) with stirring at 50° C. After refluxing for 1.5 hours, the mixture was cooled to ambient temperature. To the mixture containing benzoyl isothiocyanate was added dropwise a solution of 2-phenoxyaniline (47.6 g) in anhydrous acetone (300 ml). The reaction mixture was refluxed with stirring for 1.5 hours and then concentrated under reduced pressure to give crystals, which were washed twice with water and dried to give crystalline 1-(2-phenoxyphenyl)-3-benzoylthiourea.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:39](=[CH:40][CH:41]=2)[O:38][C:15]2([CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:32]=[C:31]5[C:26]([CH:27]=[CH:28][N:29]=[C:30]5[CH:33]5[CH2:35][CH2:34]5)=[C:25]([O:36][CH3:37])[CH:24]=4)=[O:22])[CH2:17][CH2:16]2)[CH2:14][C:13]3=[O:42])[CH:5]=1.C1COCC1.[OH-].[Na+]>CO.C(Cl)(Cl)Cl.Cl>[CH:33]1([C:30]2[C:31]3[C:26](=[C:25]([O:36][CH3:37])[CH:24]=[C:23]([C:21]([N:18]4[CH2:19][CH2:20][C:15]5([CH2:14][C:13](=[O:42])[C:12]6[C:39](=[CH:40][CH:41]=[C:10]([C:6]7[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=7)[C:3]([OH:43])=[O:2])[CH:11]=6)[O:38]5)[CH2:16][CH2:17]4)=[O:22])[CH:32]=3)[CH:27]=[CH:28][N:29]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1cccc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OC)c5ccnc(C6CC6)c5c4)CC2)O3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cccc(C(=O)O)c4)ccc2O3)cc2c(C3CC3)nccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-{1′-[(1-Cyclopropyl-5-methoxy-isoquinolin-7-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}benzoic acid methyl ester (2.00 g, 3.47 mmol) was dissolved in MeOH (20 mL), THF (10 mL) and 1N NaOH aq. (6 mL) was added thereto. After stirred at room temperature for 3 days, the reaction mixture was diluted with CHCl3, MeOH and 1N HCl aq. (6 mL). The aqueous layer was extracted with CHCl3 and the combined organic layer was dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc=5/5 to 0/10, then CHCl3/MeOH=10/0 to 88/12) to obtain the intended compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.36 (1.0H, d, J=5.9 Hz), 8.13 (1.0H, s), 8.07 (1.0H, s), 7.99-7.94 (2.0H, m), 7.93-7.85 (2.0H, m), 7.74 (1.0H, d, J=5.9 Hz), 7.60-7.53 (1.0H, m), 7.23 (1.0H, d, J=9.0 Hz), 7.19 (1.0H, s), 4.43-4.25 (1.0H, br m), 4.01 (3.0H, s), 3.67-3.13 (3.0H, m), 2.98-2.87 (1.0H, m), 2.95 (2.0H, s), 2.18-2.05 (1.0H, br m), 2.00-1.78 (3.0H, m), 1.16-1.01 (4.0H, m). MS [M+H]+=563.