Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:4](=[O:8])[CH:5]([Br:7])[CH3:6])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:9][CH:10]1[O:14][CH2:15][CH2:16][CH2:13][CH2:12][O:11]1)[C:4](=[O:8])[CH:5]([Br:7])[CH3:6])[CH3:2]
Reactant: CCOC(CN(CC)C(=O)C(C)Br)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC1OCCCCO1)C(=O)C(C)Br

Procedure:
N-Ethyl-N-(2,2-diethoxyethyl)-α-bromoproprionamide (10 grams), butandiol-1,4 (3 ml) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-ethyl-N-(1,3-dioxepan-2-ylmethyl)-α-bromoproprionamide.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[C:23]3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[C:18]([N+:32]([O-])=O)[CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>[Pd].CO>[NH2:32][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH2:15][N:14]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cccc2-c2nnn[nH]2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cccc2-c2nnn[nH]2)c(N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
A mixture of 2-butyl-7-methyl-3-[3-nitro-4-[2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-3H-imidazo[4,5-b]pyridine (145 mg), 10% palladium on carbon (30 mg), and methanol (5 ml) was stirred at room temperature for 5 hours under hydrogen atmosphere (4 atom). After vacuum filtration, the filtrate was evaporated in vacuo to give a yellow residue of 3-[3-amino-4-[2-(1H-tetrazol-5-yl)1-pyrrolyl]benzyl]-2-butyl-7-methyl-3H-imidazo[4,5-b]pyridine (130 mg). This residue was treated with acetic anhydride (1 ml) and pyridine (2ml) at room temperature for 2 hours. The reaction mixture was evaporated in vacuo and purified by preparative thin layer chromatography (ethyl acetate-acetic acid=19:1) to give a brownish viscous oil (65 ml). To a solution of the oil in ethanol (2ml) was added a solution of sodium hydrogencarbonate (12.8 mg) in water (1 ml) and the mixture was evaporated in vacuo. The residue was dissolved in water (2 ml) and lyophilized to afford sodium salt of 3-[3-acetamido-4-[2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-butyl-7-methyl-3H-imidazo[4,5-b]pyridine (65 mg) as an amorphous powder.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:23]([C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:33])=[C:24]=[O:25]>C1(C)C=CC=CC=1>[CH:1]1([N:7]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[C:24]([NH:23][C:26]2[C:27]([CH3:33])=[CH:28][CH:29]=[CH:30][C:31]=2[CH3:32])=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C)c1N=C=O
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)N(c1c2ccccc2nn1-c1ccccc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 2-isocyanato-1,3-dimethyl-benzene ([28556-81-2]) in toluene for 72 h under reflux conditions to give the title compound as yellow oil. MS: m/e=439.3 [M+H+].
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1
Reactant: OC1CCCNC1
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1CCCN(CC2COc3ccccc3O2)C1
Temperature: 153 °C

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (2.26 g, 9.88 mmol), piperidin-3-ol (1.0 g, 9.88 mmol) and K2CO3 (6.8 g, 49.43 mmol) in DMF (30 ml) was heated under microwaves at 153° C. for 120 min to give the crude title compound after the usual work-up. The product was purified by column chromatography (DCM/MeOH, 98:2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH3:37])[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][NH:16]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[N:13]([S:30]([O-:33])(=[O:32])=[O:31])[C:12]2=[O:34])=[O:9])[N:6]=1.[Na+].[H][H]>O.O1CCCC1.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH3:37])[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][NH2:16])[N:13]([S:30]([OH:33])(=[O:31])=[O:32])[C:12]2=[O:34])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1CNC(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN)c1csc(N)n1

Procedure:
In a mixture of 15 ml of water and 15 ml of tetrahydrofuran is dissolved 203 mg of sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(p-nitrobenzyloxycarbonylaminomethyl)-2-oxoazetidine-1-sulfonate (syn-isomer), followed by addition of 190 mg of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere at room temperature for 3 hours. The catalyst is filtered off and the filtrate is washed with ethyl acetate and concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column and lyophilized to give a colorless powder. The powder is rechromatographed on a Sephadex LH-20 column and lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-aminomethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:40])[C:38]5[CH:37]=[CH:36][C:35]([N:32]6[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]6)=[CH:43][CH:42]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCN(c5nccc6c5CCO6)CC4)CC3)cc2)CC1

Procedure:
The title compound, white solid (95 mg, 71%), MS (ISP) m/z=533.3 [(M+H)+], mp 236° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-(4-methyl-piperazin-1-yl)-benzoic acid.
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].O>CN1C(=O)CCC1>[O:13]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: [O-]c1ccccc1
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1nnc2ccc(Oc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 200 mg) were initially charged dissolved in NMP (4 ml). Thereafter, sodium phenoxide (185 mg) was introduced at RT. After stirring at RT for one hour, the reaction was completed by heating to 55° C. for 2 h. Subsequently, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The crude product was purified using silica gel with a dichloromethane/methanol gradient. 38 mg of the title compound were obtained in solid form. LC-MS rt: 0.80 min [M+H]+: 228.1 (met. a)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH3:12])[CH:5]=1)[CH3:2].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCCl>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:19])[CH3:12]
Reactant: CCOc1cccc(OCC)c1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CCOc1ccc(C(=O)CCC(=O)O)c(OCC)c1
Reaction time: 1 h

Procedure:
A mixture of m-diethoxybenzene (22 g.) and succinic anhydride (15 g.) was dissolved in 1,2 -dichloroethane and the resultant solution was stirred and treated with powdered aluminum chloride (30 g.), added gradually during 1 hour with external cooling to keep the reaction temperature at 10°C. The reaction mixture was stirred for 1 hour further, poured into water and the solvent was boiled off. The remaining oily suspension crystallized on stirring and cooling and the solid was collected and dried (Yield 15.5 g.). It has m.p. 139°-141°C after crystallisation from toluene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14](N3CCOCC3)[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:42](Cl)(=[O:44])C.C(=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=3)[O:15][CH:14]([O:44][CH3:42])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1cc(C2CC(N3CCOCC3)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CC(OC)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of [4-(3-bromo-4,5-dimethoxyphenyl)-2-morpholin-4-yl-chroman-7-yl]-dimethyl-amine (10 mg; 0.021 mmol) and p-toluene sulphonic acid (8 mg) in methanol (1 ml) was stirred overnight at room temperature. The mixture was cooled to 0° C. Acetyl chloride (10 μl) was added and the reaction was stirred at room temperature for 0.5 h. TLC showed formation of product. Another 10 μl of acetyl chloride was added at 0° C., and the mixture was stirred for 0.5 h at room temperature. It was neutralized with saturated sodium bicarbonate and extracted with dichloromethane. The extract was washed with saturated sodium chloride solution, dried and evaporated. The title compound was obtained by passing the crude product through a bond-elute (hexane:ethyl acetate=9:1 as eluent) (yield: 51%). 1H NMR (acetone-d6): 7.00, 6.99, 6.97 and 6.93 (d each, J=1.8 Hz; 2H), 6.54 (t, J=9.6 Hz; 1H), 6.28-6.31 (two doublets overlapped, J=8.5 Hz; fine splitting J=2.2 Hz; 1H), 6.22-6.23 (two doublets, J=3.3 Hz; 1H), 5.18 (t, J=2.5 Hz) and 5.12 (dd, J=2.4, 7.8 Hz) (1H), 4.08-4.15 (m, 1H), 3.87, 3.84, 3.80 and 3.79, (s each, 6H), 3.53 and 3.47 (s each, 3H), 2.91 and 2.90 (s each, 6H), 2.29-2.35 (m) and 1.98-2.19 (m, overlapping with acetone signal) (2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:25])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Temperature: 100 °C

Procedure:
25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, and 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 Å molecular sieve were added. The mixture was heated at reflux for 2 d (bath temperature 100° C.). The mixture was then concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator with dry ice-cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate 9:1, 4:1). This gave 20.81 g of the title compound (54% of theory).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[C:30]([Cl:31])=[CH:29][C:28]2[C:23](=[C:24](O)[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:20])[CH3:17].O>N1C=CC=CC=1>[CH2:16]([O:18][C:19]([C:21]1[C:30]([Cl:31])=[CH:29][C:28]2[C:23](=[C:24]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cc2c(O)cccc2cc1Cl
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(OS(=O)(=O)C(F)(F)F)cccc2cc1Cl
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (2.46 g, 8.73 mmol, 1.2 equiv) was added at −20° C. under an atmosphere of argon to a solution of 3-chloro-8-hydroxy-naphthalene-2-carboxylic acid ethyl ester (1.82 g, 7.28 mmol) in pyridine (55 ml). After 1 hour at 0° C., an additional portion of trifluoromethanesulfonic anhydride (2.46 g, 8.73 mmol, 1.2 equiv) was added, and stirring was continued at 0° C. for another 1.5 hours. Cold water (4° C., 100 ml) was carefully added, and the reaction mixture was extracted with EtOAc (1 liter in total). The combined organic layers were washed with concentrated aqueous NH4Cl solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (slow gradient of hexane/EtOAc 100:0 to 90:10) afforded the title compound (2.45 g, 88%, inseparable 1:1.3 mixture of regioisomers A:B) as an oil. 1H NMR (400 MHz, CDCl3): δ=8.56 (s, 1H isomer B), 8.40 (s, 1H isomer A), 8.12 (s, 1H isomer A), 8.01 (s, 1H isomer B), 7.93-7.91 (m, 1H isomer A), 7.81 (d, J=8.6 Hz, 1H isomer B), 7.62-7.51 (m, 2H isomer A+2H isomer B), 4.47 (q, J=7.1 Hz, 2H isomer A+2H isomer B), 1.45 (t, J=7.1 Hz, 3H isomer A+3H isomer B). 19F NMR (377 MHz, CDCl3): δ=−73.02. MS (ES+): 383 (M+H)+.
Reaction SMILES: O=C(C)CC[S:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:7])=[O:6].C[O-:16].[Na+:17]>C1COCC1.CO>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][S:5]([O-:16])(=[O:7])=[O:6].[Na+:17]
Reactant: C[O-]
Reactant: COC(=O)CCS(=O)(=O)CCC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension of 12 (141 g, 636 mmol) in THF (1.2 L) and MeOH (700 ml) in an ice bath was added slowly sodium methoxide (144 ml of a 25% solution in MeOH, 1.05 equiv). At the end of the addition, the bath was removed and the mixture stirred at r.t. for 1 h. The solvents were than evaporated and the remaining solid was triturated in ether containing a small amount of EtOAc. The slightly hygroscopic white solid was filtered and dried under high vacuum o.n. to yield 108.7 g (98%) of 13.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N:21]1([CH:2]([CH3:4])[CH2:1][C:5]2[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc(C2=C(CC(C)N3CCCC3)C(=O)NCCC2)c1

Procedure:
The solution of 1.36 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 0.52 g of pyrrolidine and 0.1 g of p-toluenesulfonic acid hydrate in 10 ml of benzene is refluxed with water separation for 4 hours and evaporated. The residue is dissolved in 15 ml of ethanol and the solution hydrogenated over 0.1 g of platinum oxide at atmospheric pressure and room temperature. The mixture is filtered, the filtrate evaporated and the resulting oil dissolved in 2 N hydrochloric acid. The solution is washed with benzene, basified with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and the residue recrystallized from petroleum ether and hexane, to yield the 3-(2-pyrrolidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 94° to 96°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:20][NH2:21])[CH3:19].N1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:21][O:20][CH2:18][CH3:19])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCON
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 91.8 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22mmol) and O-ethylhydroxylamine hydrochloride (6.4 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.5 g, 93%) was isolated as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)=[C:8]1[CH2:7][CH2:6]2.B(Br)(Br)Br.CCOCC>ClCCl>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][N:10]=[C:9]3[C:22]4[C:5]([CH2:6][CH2:7][C:8]=23)=[CH:4][C:3]([OH:2])=[CH:24][CH:23]=4)=[CH:14][CH:15]=1)[CH2:20][CH3:21]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(OC)ccc2-3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: CCCc1ccc(-c2onc3c2CCc2cc(O)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
To 7-methoxy-3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 9B, 0.35 g, 1.096 mmol) in dichloromethane (10 mL) was added boron tribromide (1.425 mL, 1.425 mmol) dropwise over a period of 3 min. at 0° C. Approximately 2 min. after the addition was complete a white solid separated out. The reaction mixture was allowed to come to room temperature over a period of 10 min. and then was stirred at room temperature for 30 min. Additional boron tribromide (2 mL) was added at room temperature and the contents were stirred at room temperature for 1.5 h. Additional boron tribromide (10 mL) was added at room temperature. The heterogeneous solution become homogenous and brown. The contents were stirred at room temperature for an additional 3 h, then cooled to 0° C. and quenched by the very slow addition of MeOH (˜5 mL). The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (50 mL) and water (20 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield a greenish solid. Trituration with dichloromethane (2 mL) and ether (10 mL) followed by sonication for 3 min. yielded an off-white solid which was collected by filtration and washed with ether (2×5 mL) to afford 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (0.115 g). The compound had an HPLC retention time=3.80 min (condition C); LC/MS M+1=306. 1H NMR (400 MHz, MeOD) δ ppm 7.72 (dd, J=8.16, 1.38 Hz, 3H) 7.38 (d, J=8.28 Hz, 2H) 6.76-6.84 (m, 2H) 2.93-3.07 (m, 4H) 2.65-2.72 (m, 2H) 1.65-1.78 (m, 2H) 0.99 (t, 3H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([C:22]4(O)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:25]1[CH2:24][CH:23]=[C:22]([C:20]2[S:21][C:17]([C:13]3[N:8]4[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[C:7]4=[N:15][C:14]=3[CH3:16])=[C:18]([CH3:29])[N:19]=2)[CH2:27][CH2:26]1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(C4(O)CCOCC4)nc3C)c(C)nc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4=CCOCC4)nc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
150 mg of 4-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-tetrahydro-pyran-4-ol (0.36 mmol) is dissolved in 5 ml of CH2Cl2 and 112 mg of triethylsilane (0.96 mmol) and 717 mg of trifluoroacetic acid (6.3 mmol) are added. The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is stirred under reflux for 1 h and cooled down to room temperature. The solvent is removed in vacuo. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 64 mg of the title compound. Yield 45%. mass spectrum (m/e): 397 (M+1). 6.94 (s, 1H), 6.71 (s, 1H), 4.41 (d, J=2.6 Hz, 2H), 3.98 (t, J=5.3 Hz, 2H), 3.43 (m, 1H), 2.62 (s, 3H), 2.75 (m, 2H), 2.56 (s, 3H), 2.37 (s, 3H), 1.86 (m, 4H), 0.92 (t, J=8.2 Hz, 6H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[OH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(CO)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2ccc(CO)cc2)nn1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-Hydroxymethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (4.35 g, 9.42 mmol) and lithiumhydroxide-hydrate (1.976 g, 47.1 mmol) in 80 mL MeOH and 80 mL water was stirred at 30° C. for 3 h. The methanol was evaporated in vacuo. The residual aqueous layer was washed with ethyl acetate, acidified with 1 N aq. HCl and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and evaporated to yield the crude product which was used in the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) 13.1 (broad s, 1H), 8.76 (s, 1H), 7.27-7.39 (m, 4H), 5.63 (s, 2H), 5.20 (t, 1H), 4.48 (d, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[N:4]=1)[CH3:2].[CH:18]1([Mg]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH:8]([C:7]2[C:3]([CH2:1][CH3:2])=[N:4][N:5]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[CH:6]=2)[OH:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCc1nn(-c2cccc(OC)c2)cc1C=O
Solvent: C1CCOC1
Product: CCc1nn(-c2cccc(OC)c2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (20 mL) of 3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1.9 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (12.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give a crude product (2.6 g, quantitative) of the title object compound as a pale-yellow oil.