Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:9]3[N:10]([CH:11]=[CH:12][N:13]=3)[C:3]=12.CC(C)([O-])C.[K+].[CH3:27][N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]=[C:29]1S(C)(=O)=O.O>CC(N(C)C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:29]4[N:28]([CH3:27])[C:32]5=[N:33][CH:34]=[CH:35][CH:36]=[C:31]5[N:30]=4)=[CH:16][CH:15]=3)[C:9]3[N:10]([CH:11]=[CH:12][N:13]=3)[C:3]=12
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Cc1ccnc2c1n1ccnc1n2-c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccnc2c1n1ccnc1n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a solution of 4-(5-methyl-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (238 mg) in DMA (4 ml) was added potassium tert-butoxide (112 mg) at room temperature. After stirring for 10 min, 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (211 mg) was added, and the obtained mixture was stirred at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (THF) and recrystallized from hexane/THF to give the title compound (229 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)=[CH2:3].CN1C=CN=C1.[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C1(C)C=CC=CC=1>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:3])[CH2:1][CH:21]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(C)c1ccc(C(C)=O)cc1
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1(C)c1ccc(C(C)=O)cc1
Yield: 21.6 %

Procedure:
To a stirred solution of 1-[4-(1-methylethenyl)phenyl]ethanone (711 mg, 4.44 mmol, trans) (Org. Lett., 2002, 4(1), 107-109), N-methylimidazole (1.06 ml, 13.3 mmol) and Co(TPP)(89 mg, 0.13 mmol) in toluene (10 ml) was added ethyl diazoacetate (0.65 ml, 6.21 mmol) in one portion at ambient temperature. The same procedure as described in Example 2H was performed to give the title compound (236 mg, 22%) as dark yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][CH:18]=2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10].O.[CH3:31]N(C)C=O>>[OH:3][C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][CH:18]=2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:10][CH3:31]
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3cc(O)c(O)c([N+](=O)[O-])c3)cs2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1c(O)cc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mg of sodium hydride (60%) were added to a solution of 0.5 g of N-[4-(3,4-dihydroxy-5-nitro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide in 5 ml of dimethylformamide. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was chromatographed on 60 g of Kieselgel 60 with methylene chloride/acetone/formic acid (90:10:2.5) as the eluent. The product-containing fractions were concentrated and, after boiling with 20 ml of diethyl ether, yielded 0.17 g of N-[4-(3-hydroxy-4-methoxy-5-nitro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as orange colored crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:11]=1.B(OC(C)C)(OC(C)C)[O:38]C(C)C.Cl.[Cl-].[Na+]>O1CCCC1.CCCCCC.C(C1C=CC=CC=1)C.O1CCCC1>[F:9][C:10]1[C:15]([OH:38])=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:11]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(-c3cccc(F)n3)cc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(O)c(F)n3)cc2)cc1
Reaction time: 4 h

Procedure:
7.95 ml (15.90 mmol) of a 2-molar lithium diisopropylamide solution in tetrahydrofuran/hexane/ethylbenzene are added dropwise at -78° C. to 5.00 g (13.25 mmol) of 2-fluoro-6-[4-(4-octyloxyphenyl)phenyl]pyridine (prepared as described in Example 6) in 1000 ml of tetrahydrofuran, and the mixture is stirred for 4 hours. 5.98 (31.80 mmol) of triisopropyl borate in 10 ml of tetrahydrofuran are then added dropwise at -78° C., and the reaction mixture is stirred overnight, during which it warms to room temperature. After addition of 20 ml of 10% hydrochloric acid and stirring at room temperature for 1 hour, sodium chloride solution is added, the mixture is extracted with ether, the ether phase is washed with sodium chloride, dried over sodium sulfate, filtered and concentrated. The residue is taken up in 200 ml of tetrahydrofuran, boiled with 40 ml of 17.5% hydrogen peroxide solution at 80° C. for 2 hours and then distributed between water and ether. The ether phase is washed with sodium sulfite solution and water, dried over sodium sulfate, filtered, evaporated to dryness, and the residue is chromatographed on silica gel using 8:2 toluene/THF, giving 1.7 g of 2-fluoro-3-hydroxy-6-[4-(4-octyloxyphenyl)phenyl]pyridine. ##STR25##
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:20])[NH:9][C:10]([Cl:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br-].[Li+].[CH3:25]I>O.CN(C)C=O.COCCOC>[CH3:25][N:9]1[C:10]([Cl:19])=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:20]
Reactant: CI
Reactant: O=c1[nH]c(Cl)c(-c2ccccc2)nc1-c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cn1c(Cl)c(-c2ccccc2)nc(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 3,5-diphenyl-6-chloro-1H-pyrazin-2-one (1.2 g ; prepared by the method of Cheeseman et al, J. Chem. Soc. Chem. Comm. 1971, (18), 2977-2979) in 4:1 ethylene glycol dimethylether:dimethylformamide (25 cm3)was added sodium hydride (0.28 g). The reaction was stirred for 5 minutes at 0° C. under nitrogen whereupon lithium bromide (1.17 g) was added. After a further 5 minutes stirring at room temperature, under nitrogen, methyl iodide (4.78 g) was added. The mixture was stirred at room temperature overnight under nitrogen. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was separated, dried over sodium sulphate and evaporated in vacuo. The residue was subjected to chromatography on silica gel using ethyl acetate as eluant to afford 1-methyl-3,5-diphenyl-6-chloro-1H-pyrazin-2-one as a yellow solid (1.2 g; 60%). Found C, 68.98; H, 4.31 ; N, 8.98% C17H13N2OCl requires C, 68.81; H, 4.42; N, 9.44%.m/e (ES+) 297/299 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1B(O)O.[F-].[Cs+]>C(COC)OC>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:22]2[CH:21]=[CH:20][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
Tetrakis triphenyphosphine palladium (65 mg, 7.4 mol %) was added to a dimethoxy ethane (5.4 mL) solution of (4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (447 mg, 1.5 mmol), 2-naphthaleneboronic acid (286 mg, 1.67 mmol) and cesium fluoride (505 mg, 3.33 mmol). The reaction was flushed with nitrogen and heated in an oil bath to 100° C. while stirring for 3 hours. The reaction was then diluted with ethyl acetate and extracted with water, 1 M sodium hydroxide, water and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with 5% ethyl acetate in hexanes to give the title compound as a clear oil (273 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.01-7.38 (m, 11H), 3.72 (s, 3H), 3.69 (2H)
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:29][CH2:30][CH:25]([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc3ccccc3c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-naphthyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 74% overall yield. mp. 171°-172°. FDMS m/e=400 (M+ of free base). α[D]589 =-13.51 (c=1.04, methanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27](B(O)O)[C:28]([F:31])=[N:29][CH:30]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>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.O1CCOCC1>[F:31][C:28]1[N:29]=[CH:30][C:25]([CH2:24][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[CH:26][C:27]=1[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(C)nc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)n1
Temperature: 80 °C
Yield: 73.2 %

Procedure:
1,4-dioxane (15 mL) and H2O (3.00 mL) were added to a mixture of 2-chloro-4-methyl-6-(methylthio)-1,3,5-triazine (0.560 g, 3.19 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (1.03 g, 3.04 mmol), Na2CO3 (0.805 g, 7.59 mmol), and Pd(Ph3P)4 (0.175 g, 0.152 mmol) and the stirred suspension was heated at 80° C. overnight. After cooling, the mixture was passed a short plug of Na2SO4, washed with EtOAc(×2) and concentrated. The residue was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (hexanes to 30% ethyl acetate in hexanes) to give tert-butyl 4-((6-fluoro-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.9676 g, 74%) as a white solid. LCMS (API-ES) m/z 435 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=9.00 Hz, 1H) 8.30 (s, 1H) 3.58 (s, 2H) 3.44 (br. s., 4H) 2.66 (s, 3H) 2.64 (s, 3H) 2.43 (d, J=4.50 Hz, 4H) 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C=O)C.[Pd].[Cu]I>[Br:8][C:6]1[N:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cu]I
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 3,5-Dibromo-pyrazin-2-ylamine (3.00 g, 11.86 mmol) in DMF (35 ml) was added triethylamine (16 ml), then tetrakistriphenylphine palladium (0) (685 mg, 0.59 mmol) and copper(I) iodide (271 mg, 1.42 mmol) were added sequentially. Finally trimethylsilylacetylene (2.0 ml, 14.3 mmol) was added dropwise. The reaction mixture was stirred at 120° C. for 30 minutes and then directly adsorbed onto silica gel. Purification by flash chromatography on silica gel with a gradient of ethyl acetate/hexane afforded the title compound (2.30 g, 71% yield) as yellow oil. MS: m/z 270.0/272.0 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[Cl:19])=[O:23])=[N:16][CH:17]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1nc2cc(Cl)c(-c3ccc(N)nc3)cc2o1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(Cl)c(-c3ccc(NC(=O)c4ccccc4Cl)nc3)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 5-(5-chlorob-2-methylenzoxazol-6-yl)-2-pyridylamine (36) (19 mg, 0.073 mmol) and 2 mg DMAP in 2 ml DCM was added 2-chlorobenzoyl chloride (19 μl, 0.14 mmol) followed by addition of DIEA (64 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (140 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 20.6 mg 37 as pale yellow solid. (yield: 71%).
Reaction SMILES: ClCCCCC=O.C([NH:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]Cl)=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=2)[CH:13]=1)(=O)C.N1CCCCC1.[NH:44]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[NH2:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][N:44]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=2)[CH:13]=1
Reactant: C1CCCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Agent: O=CCCCCCl
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCCCCC2)cc(OC)c1

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-chloropentan-1-one and piperidine with azacycloheptane, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-(azacyclohept-1-yl)pentan-1-one, m.p. 137°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[NH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CC(C)CCN
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCC(C)C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 1-amino-3-methylbutane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]([C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Br:16])=[CH:11][C:10]=1[S:17]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH3:31])([CH3:30])[CH2:22][CH2:21]1)(=[O:19])=[O:18])C(OC)=O.[Na+].[Cl-]>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Br:16])=[CH:11][C:10]=1[S:17]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH3:30])([CH3:31])[CH2:22][CH2:21]1)(=[O:19])=[O:18]
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)c(Br)cc1S(=O)(=O)N1CCC(C)(C)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1cc(Cl)c(Br)cc1S(=O)(=O)N1CCC(C)(C)c2ccccc21
Temperature: 25 °C
Yield: 79.7 %

Procedure:
2-[4-Bromo-5-chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-malonic acid dimethyl ester (0.72 g, 1.32 mmol) was heated at 120° C. for 5 hrs in DMSO which contained NaCl (153.5 mg, 2.65 mmol) and 2 drops of water. After cooling to rt, the mixture was extracted with ethyl acetate, washed with water and brine, and was dried over MgSO4. Filtration and concentration yielded a residue which was purified via silica gel flash column chromatography eluting with hexane/ethyl acetate (100/15) to give 2-[4-bromo-5-chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-acetic acid methyl ester (512 mg). MS: 487.9 (M+H)+; tR=2.75 min (method 1)
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:15]=2[N:14]([CH2:30][C:31]2[N:32]=[CH:33][N:34](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:35]=2)[C:13]1=[O:55])=O)C1C=CC=CC=1.Br.C(OCC)(=O)C>C(O)(=O)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:15]=2[N:14]([CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[C:13]1=[O:55]
Reactant: Cc1cccc2c1N(Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn1)C(=O)C(NC(=O)OCc1ccccc1)N=C2C1CCCCC1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cccc2c1N(Cc1c[nH]cn1)C(=O)C(N)N=C2C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1-(1-triphenylmethylimidazol-4-yl)methyl-1H-1,4-benzodiazepin-2-one (0.5 g) and 30% hydrobromic acid in acetic acid (2.0 ml) was stirred at room temperature overnight. The reaction mixture was poured into a mixture of an ice and ethyl acetate under stirring. The separated water layer was washed with ethyl acetate once, and neutralized with a saturated aqueous solution of sodium bicarbonate. The resultant aqueous mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate. Removal of the solvent in vacuo afforded (3RS)-3-amino-5-cyclohexyl-2,3-dihydro-1-(imidazol-4-yl)methyl-9-methyl-1H-1,4-benzodiazepin-2-one (174 mg, 72.1%) as a crystalline powder.
Reaction SMILES: [CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C1C=CC=CC=1>[CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[S:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1CCCCCC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: CCCCCCCCCCCCN1CCCCCC1=S
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 5g (17.7mmol) of 1-n-dodecylazacycloheptan-2-one in 150ml of benzene was added 4.18g (9.4mmol) of phosphorus pentasulfide and the mixture was refluxed for 1 hr. After cooling to room temperature, the mixture was filtered and the solid was washed with chloroform and ethanol. The filtrate was concentrated in vacuo and the residue was subjected to flash chromatography, (silica; (95:5)V/V hexane/ethyl acetate) to give 2.11g (40%) of 1-n-dodecylazacycloheptane-2-thione.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:8]=2[O:7]1)C.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=1[CH2:33][CH2:34][CH3:35]>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][O:16][C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:3])=[O:17])[O:7][C:8]=3[CH:15]=2)=[C:24]([CH2:33][CH2:34][CH3:35])[C:25]=1[OH:32])(=[O:31])[CH3:30]
Reactant: CCOC(=O)CC1CCc2ccc(O)cc2O1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2ccc3c(c2)OC(CC(=O)O)CC3)ccc(C(C)=O)c1O
Yield: 40.5 %

Procedure:
A 0.9 g sample of racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester was alkylated with 3 g of 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone using the procedure described in Example 31. The crude product (2.6 g ) was chromatographed on 50 g of silica gel giving 1.2 g of the desired ester as a pale-yellow oil (eluted with 19:1 toluene-ethyl acetate). This material was saponified with 2.0 g of lithium hydroxide monohydrate using the procedure described in Example 31. The crude acid (1.1 g) was chromatographed on 50 g of silica gel. Elution with 2:1 and 1:1 toluene-ethyl acetate afforded 682 mg (40.5%) of racemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-acetic acid as a pale-yellow solid, mp 107°-109.5° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1.[F-].[K+]>CS(C)=O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[N:24]1[CH:28]=[CH:27][CH:26]=[N:25]1)=[O:13])[CH2:8]2
Reactant: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: c1cn[nH]c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1-n1cccn1
Yield: 40.8 %

Procedure:
In a Personal Chemistry microwave process tube (Biotage AB, Sweden), 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 36, 100 mg, 0.30 mmol), pyrazole (41 mg, 0.60 mmol), KF (35 mg, 0.60 mmol) and DMSO (2 mL) were well mixed. The tube was sealed with a septum and was submitted to 150 W microwave irradiation using a Personal Chemistry Microwave Synthesis system (Biotage AB, Sweden) at 230° C. for 20 minutes. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, concentrated in vacuo and purified by C-18 reversed phase prep-HPLC with a gradient of 10-100% acetonitrile/water to give 2′-tert-butyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid adamantan-2-ylamide (45 mg, 41%). Mass spectrum: m/z: 368.2 (M+1).