Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[O:8]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccccc1
Reactant: COC(=O)CC(=O)Cl
Solvent: ClCCl
Product: COC(=O)CC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-3-oxopropanoate (2.0 g, 14.7 mmol) in dry DCM (100 ml) was added aniline (2.68 g, 3.6 mmol) and the reaction mixture was stirred at 0° C. for 1 hr, evaporated then dissolved in EtOAc, washed with dilute HCl, NaHCO3, and brine. The organic phase was collected, dried over sodium sulfate, filtered and the solvent was evaporated to afford methyl 3-oxo-3-(phenylamino)propanoate as a brown oil which was used without further purification (2.8 g, 100%, crude). To a solution of this material (2.8 g, 14.5 mmol) in THF (40 ml) and water (20 ml) was added NaOH (1.16 g, 29 mmol) and the reaction mixture was stirred overnight, evaporated (to remove the THF) and then extracted with Et2O. The aqueous phase was acidified to pH 1 and extracted with EtOAc. The extract was dried over Na2SO4, filtered and evaporated to afford the title compound 1 as a brown solid, which was used without further purification (2.0 g, 77% yield). MS (m/z): 18.0 (100%) (M+H), 202.0 (44%) (M+Na).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:47]=[CH:46][C:15]([O:16][CH2:17][C:18]#[C:19][C:20]2(O)[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[O:23][CH2:22][C:21]2([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)[CH3:34])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OCCCCCCCC#CC1C2C(=CC(OC)=CC=2)SCC1(C1C=CC(OC)=CC=1)C)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]#[C:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[O:23][CH2:22][C:21]2([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:39][CH:40]=2)[CH3:34])=[CH:46][CH:47]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCOc2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2C#CCOc2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)cc1

Procedure:
The title compound was prepared from 4-{3-[4-(3-t-butyldimethylsilyloxypropyl)phenoxy]-1-propynyl}-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman-4-ol according to the same method for the synthesis of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman described in International Patent Appln. No. PCT/KR 97/00265.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O:5][CH3:6])=[O:4].CC(C)([O-])C.[K+].[CH2:21](Br)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH3:1][O:2][P:3]([CH:7]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O:5][CH3:6])=[O:4]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: BrCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(CCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 60.8 %

Procedure:
118 g of tert-butyl dimethylphosphonoacetate were dissolved in 875 ml of dried dimethylformamide under a nitrogen atmosphere. 58.9 g of potassium tert-butoxide were added to the solution while cooling in ice. The reaction mixture was subsequently heated to 60° C. for a short time and then allowed to cool to room temperature. A solution of 104.9 g of phenethyl bromide in 110 ml of dimethylformamide was added dropwise to the reaction mixture. The reaction mixture was then heated at 60° C. for 2 hours. For working up, the dimethylformamide was substantially evaporated off under reduced pressure, and the remaining residue was dissolved in methyl tert-butyl ether. The solution was acidified with aqueous potassium bisulfate solution. The organic phase was then separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography on 3 kg of silica gel using dichloromethane/methyl tert-butyl ether (4:1) as eluent. 105.1 g of pure tert-butyl 2-(dimethylphosphono)-4-phenyl-n-butyrate were obtained as an oily product.
Reaction SMILES: [CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:31])[O:30][CH2:29]1>>[CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[CH2:23][CH2:22]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)c(F)c1
Reactant: CC1(C)CO1
Product: CC(C)(O)CN1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3F)on2)C2CC2)CC1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 1,1-dimethyloxirane following a procedure analogous to that described for Intermediate 2. LC (method 3): tR=1.21 min; Mass spectrum (ESI+): m/z=427 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]4[N:27]=[CH:26][N:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[N:24]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH:34]([B-](F)(F)F)=[CH2:35].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>COCCOC.O>[CH3:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([CH:34]=[CH2:35])=[CH:7][N:6]2[C:8]=1[C:12]1[S:13][C:14]([C:23]2[N:27]=[CH:26][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1
Reactant: C=C[B-](F)(F)F
Reactant: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C=Cc1ccc2nc(C)c(-c3nc(-c4ccccc4)c(-c4ncn(C5CCCCO5)n4)s3)n2c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a suspension of 6-bromo-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine (1.04 g, 2.0 mmol) obtained by similar manner with Example 117-B(i) in DME (70 mL) and water (14 mL), were added potassiumvinyltrifluoroborate (410 mg, 3.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (170 mg, 0.2 mmol) and cesium carbonate (1.90 g, 6.0 mmol) under a nitrogen atmosphere, and the mixture was stirred at 95° C. for 4 h. The reaction mixture was allowed to cool to rt, and then was added EtOAc (40 mL). The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound (890 mg, 95%) as a gray solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[NH:13][C:12]1=[O:19])[CH2:8]2.Br[CH2:21][CH:22]1[CH2:25][CH2:24][CH2:23]1>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:13]([CH2:21][CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:12]1=[O:19])[CH2:10]2
Reactant: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)[nH]1
Reactant: BrCC1CCC1
Product: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)n1CC1CCC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-isopropyl-1,3-dihydro-imidazol-2-one (obtained in example 8, 100 mg) by alkylation with bromomethylcyclobutane (86 mg). 1-Adamantan-2-yl-3-cyclobutylmethyl-4-isopropyl-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (51 mg). MS (EI): 328.3 (M+).
Reaction SMILES: [CH2:1]([CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C(=O)C)[CH:14]=1)[C:10]([NH2:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CO>[CH2:1]([CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[C:10]([NH2:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(C(N)=O)c1cccc(OC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(C(N)=O)c1cccc(O)c1

Procedure:
To a chilled solution of 10.14 g of the mixture containing octyl 3-acetoxyphenylacetamide and 100 ml of methanol was added 12.63 ml of 5 N NaOH. The mixture was stirred at room temperature for 3 hours after which the methanol was removed in vacuuo. The residue was dissolved in 100 ml of 1 N NaOH and extracted with 50 ml of ether. The resulting aqueous phase was acidified with conc. hydrochloric acid and extracted twice with 100 ml of ether. The combined ether extracts were washed with 75 ml of water and 75 ml of brine, dried (MgSO4), filtered, and evaporated to provide 7.55 g of crude product which was recrystallized from toluene-pentane to yield 5.03 g of octyl 3-hydroxyphenylacetamide, m.p. 60°-62° C. Anal. Calc'd for C16H25NO2 : C, 73.00; H, 9.58; N, 5.32. Found: C, 72.86; H, 9.63; N, 5.16.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.C(OC([NH:17][CH:18]([CH2:23]I)[C:19]([O:21]C)=[O:20])=O)(C)(C)C.[NH2:25][C:26]1[C:31]2=[C:32]([C:36]([C:38]3[CH:39]=[C:40]([NH:44][C:45]([NH:47][C:48]4[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=4[Cl:55])=[O:46])[CH:41]=[CH:42][CH:43]=3)=[O:37])[CH:33]=[C:34](Br)[N:30]2[N:29]=[CH:28][N:27]=1.O>CC(N(C)C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[NH2:17][C@@H:18]([CH2:23][C:34]1[N:30]2[C:31]([C:26]([NH2:25])=[N:27][CH:28]=[N:29]2)=[C:32]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])=[O:46])[CH:39]=2)=[O:37])[CH:33]=1)[C:19]([OH:21])=[O:20]
Reactant: Nc1ncnn2c(Br)cc(C(=O)c3cccc(NC(=O)Nc4ccc(Cl)cc4Cl)c3)c12
Reactant: COC(=O)C(CI)NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Nc1ncnn2c(C[C@H](N)C(=O)O)cc(C(=O)c3cccc(NC(=O)Nc4ccc(Cl)cc4Cl)c3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.8 %

Procedure:
A mixture of zinc dust (300 mg) in dimethylacetamide (DMA) (0.3 mL) at 50° C. was treated with a solution of chlorotrimethylsilane/1,2-dibromoethane (7/5 v/v, 0.04 mL) and the reaction was stirred at room temperature for 30 minutes. A solution of methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (247 mg, 0.75 mmol) in DMA (1 mL) was slowly added and the reaction was stirred for 40 minutes. This mixture was added to a mixture of 95G (35 mg), PdCl2(dppf)2 (7 mg), and CuI (10 mg) in DMA (0.8 mL). The reaction was heated to 80° C. for 18 hours. Water was added and the solid precipitate was collected by filtration. The solid was treated with 33% HBr/AcOH and then concentrate. The residue was dissolved in THF/MeOH and water and treated with LiOH and stirred at room temperature for two hours. The reaction mixture was neutralized with trifluoroacetic acid and purified by preparative reversed phase HPLC to afford the desired product (1.7 mg). Compound 103 had an analytical HPLC retention time=2.906 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=528+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[C:33]1(=[O:38])[O:37][CH2:36][CH2:35][CH2:34]1.[Na].C[Si](C)(C)N[Si](C)(C)C>O1CCCC1>[OH:38][CH2:33][CH2:34][CH2:35][C:36]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:21])[NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=4)[CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1)=[O:37]
Reactant: O=C1CCCO1
Reactant: Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(CCCO)Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
30 mg (0.068 mmol) of 1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea were dissolved in 2 ml of dry tetrahydrofuran and 15 μl (0.34 mmol) of γ-butyrolactone were added. The reaction mixture was cooled to 0° C. and a solution of 680 μl (0.68 mmol) of hexamethyldisilazane sodium salt 1M in THF in 2 ml of the same solvent were added dropwise. The mixture was maintained at 0° C. for 6 hours and at room temperature overnight, then partitioned between dichloromethane and water. The organic phase was dried over sodium sulphate and evaporated. The crude was finally purified by preparative HPLC in reverse phase conditions (basic eluant), giving 20 mg (59%) of the title compound.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6][NH:5]1.[Br:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][CH2:21][N:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[C:4]1=[O:3]
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCCBr)c(=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 0.30 g, 7.4 mmol) in DMF (15 mL) under an atmosphere of nitrogen cooled to 0° C. was added methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (1.0 g, 4.9 mmol) in DMF (15 mL) dropwise. The mixture was stirred for 30 mins, then 1,3-dibromopropane (80 μL, 1.28 mmol) was added quickly and the resulting solution was stirred overnight warming to rt slowly. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 30% EtOAc/hexanes) to afford methyl 2-(3-bromopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.60 g, 38%). LC-MS: (FA) ES+ 326.
Reaction SMILES: [C:1]1([CH:7]2[C:12]3=[N:13][NH:14][C:15](=[O:20])[C:16]4[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=43)[NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCC1.CCN(CC)CC>C1COCC1>[C:1]1([CH:7]2[C:12]3=[N:13][NH:14][C:15](=[O:20])[C:16]4[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=43)[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Nc2cccc3c(=O)[nH]nc(c23)C1c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc2c3c(cccc13)NCC2c1ccccc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 1.4 %

Procedure:
A mixture of 9-phenyl-2H-pyrido[4,3,2-de]phthalazine-3,8(7H,9H)-dione (80 mg, 2.2 mmol), BH3 (0.7 mL, 1 mol/L in THF), dioxane (4 mL) in sealed tube was stirred for 2 h at 95° C. under nitrogen atmosphere. Then the mixture was treated with MeOH˜HCl (g) (0.2 mL), stirred for 20 min at 95° C. Then the mixture was cooled and adjusted to pH=8 with Et3N. The solvent was removed under vacuum and the crude was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 1:1) to obtain the title compound as a yellow solid (l 8.3 mg, yield 24%). LC-MS (ESI) m/z: 264 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.60-3.64 (m, 1H), 3.68-3.72 (m, 1H), 4.21 (t, J=5.2 Hz, 1H), 7.09-7.11 (d, J=8 Hz, 1H), 7.16-7.29 (m, 5H), 7.53-7.61 (m, 2H).
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([O-:3])=[O:2].[CH3:11][OH:12]>>[CH3:11][O:12][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: O=C1CCCCC1[N+](=O)[O-]
Reactant: CO
Product: COC(=O)CCCCC[N+](=O)[O-]

Procedure:
Commercially available 2-nitrocyclohexanone was refluxed in MeOH in presence of Amberlyst A21 to give 6-nitrohexanoic acid methyl ester 1. Reaction of 1 with N,N′-dibenzylethylenediamine diacetate and paraformaldehyde gave diazepine 2 which was firstly hydrogenated to 3 and then alkylated with t-butyl bromoacetate to give pentaester 4. Selective hydrolysis of 4 by means of LiOH in THF/H2O gave 5. Overall yield 13%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:22][OH:23].S(=O)(=O)(O)O>O>[CH3:1][C:2]([CH3:16])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: CCC1CCCCCCCCC(C)(C)C=N1
Reactant: NO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(N)CCCCCCCCC(C)(C)C=NO
Yield: 191 %

Procedure:
The procedure as described in Example 1(b) is carried out but with the use of 223 g (1 mol) of 3,3-dimethyl-12-ethyl-1-aza-cyclododecene, 82 g (0.5 mol) of hydroxylamine sulfate, 150 g of sulfuric acid and 400 ml of water. Distillation yields 245 g (0.955 mol) of 2,2-dimethyl-11-ethyl-11-amino-undecanal oxime; b.p. 155°-160° C./7 Pa.
Reaction SMILES: [CH3:1][N:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[ClH:32].C(O)C.C(=O)([O-])[O-].[NH4+:40].[NH4+]>CO>[ClH:32].[CH3:1][N:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](=[NH:40])[NH2:22])=[CH:19][CH:20]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Product: CN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C
Yield: 46 %

Procedure:
Prepared analogously to Example 32 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-sulfonic acid-N-methyl-N-phenylamide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 46% of theory, C23H23N5O3S (449.5); EKA mass spectrum: (M+H)+=450; (M+H+methanol)+=482; (M+2H)++=223.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[C@H:27]([F:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:29]([O-])([O-])=O.[Na+].[Na+].C(O)=O.C=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[C@H:27]([F:28])[CH2:26][CH2:25][N:24]([CH3:29])[CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: F[C@@H]1CCNCC[C@H]1Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Product: CN1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of Stereoisomers 1 and 2 of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoroazepan-4-yloxy)quinoline (0.023 g, 0.0511 mmol) was slurried in CH2Cl2 (3 mL). A saturated aqueous Na2CO3 solution (5 mL) was added and the mixture was stirred at ambient temperature for 0.5 hours. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The crude residue was treated with formic acid (0.289 mL, 7.66 mmol) and formaldehyde (0.0380 mL, 0.511 mmol). The mixture was stirred at 90° C. for 4 hours. The mixture was cooled to ambient temperature and carefully treated with a saturated aqueous Na2CO3 solution to adjust the mixture to about pH 11. The mixture was extracted with CHCl3 and the combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by Preparative TLC (0.5 mm, 10% MeOH/CH2Cl2 with 1% 7N NH3/MeOH) to provide the desired product (0.011 g, 55%) as a white solid. MS ESI (+) m/z 392.1 (M+1) detected.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH3:30][NH2:31]>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][NH:31][CH3:30])[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CNC/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12. 1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with methylamine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-methylamino-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 449 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][CH2:22][O:23]C(=O)C)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:19])[N:10]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][CH2:22][OH:23])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:19])[N:10]=1
Reactant: CC(=O)OCCc1cc(Cl)c(Oc2cc(C(C)C)c(=O)n(C)n2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nn(C)c1=O
Reaction time: 24 h
Yield: 101 %

Procedure:
A solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (35) (390 mg, 0.97 mmol) in methanol (4 mL) was treated with a 1N aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol) at room temperature. The reaction mixture was stirred for 24 h and was then concentrated under vacuum. The resulting residue was diluted with methylene chloride (35 mL) and was washed with a saturated aqueous sodium chloride solution (20 mL). The aqueous layer was separated and was re-extracted with methylene chloride (25 mL). The organic layers were combined and dried with sodium sulfate, filtered, and concentrated. The resulting solid was dried under high vacuum to afford 6-[2,6-dichloro-4-(2-hydroxy-ethyl)-phenoxy]-4-isopropyl-2-methyl-pyridazin-3-one (36) (350 mg, 97%) as a white solid that was used without further purification. Molecular Weight=357.2395; Exact Mass=356.0694
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][N:5]1[C:12](=[O:13])[CH:11]([C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[C:9](=[O:10])[N:8]([CH3:31])[C:6]1=[O:7]>CO.O>[CH3:4][N:5]1[C:12](=[O:13])[CH:11]([C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[N:24]=[N:25][C:26]([O:2][CH3:1])=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[C:9](=[O:10])[N:8]([CH3:31])[C:6]1=[O:7]
Reactant: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(Cl)nn3)cc2)C(=O)N(C)C1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Oc2ccc(NC(=O)C3C(=O)N(C)C(=O)N(C)C3=O)cc2)nn1

Procedure:
The equimolar amount of sodium methylate is added at room temperature to 1.0 g (0.0025 mole) of 1,3-dimethyl-5-[4-(6-chloropyridazin-3-yloxy)phenylcarbamoyl]barbituric acid in 20 ml of methanol. The mixture is heated under reflux for 5 hours, then cooled, diluted with water and filtered. The filtrate is washed with water and dried.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[NH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>ClCCl>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[O:21][C:1](=[O:2])[NH:13][C:14]=2[CH:19]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1cc(F)ccc1O
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)ccc2o1
Yield: 67 %

Procedure:
Carbonyl diimidazole (7.6 g) was added to a solution of 2-amino-4-fluorophenol (5 g, 39 mmol) in dichloromethane (0.100 ml). After 14 hours the solution was washed with 5M aqueous HCl, water, and dried over magnesium sulfate. The solution was filtered through a plug of silica and evaporated affording a white solid (4.0 g, 66%).