Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].C(N(CC)CC)C.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>ClCCl>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([O:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])=[O:25])[CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C/C=C(/C=C/CO)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(C=CCOC(=O)c1cccnc1)CC
Temperature: 0 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a mixture of (E,E)-4-ethyl-2,4-hexadien-1-ol (2.0 g), triethylamine (8 ml), and dichloromethane (15 ml) at 0° C. was added nicotinic acid chloride hydrochloride (4.23 g). The solution was stirred at 0° C. for 1.5 hours and at room temperature for 14 hours. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (chloroform) to give 4-ethyl-2,4-hexadien-1-yl 3-pyridinecarboxylate (3.3 g) as an oil.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30]O)[CH2:24][CH2:23]1)=O)(C)(C)C>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:30][CH2:29][CH2:28][CH:25]2[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Product: c1ccc(C(OCCCC2CCNCC2)c2ccccc2)cc1
Yield: 90 %

Procedure:
Using benzhydrol and 1-(tert-butoxycarbonyl)-4-piperidinepropanol, the procedure of Reference Example 23 was otherwise repeated to provide the title compound. Yield 90%.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=CC2C(=CC=C(O)C=2)C=1C(C1C=CC(OCCN2CCCCC2)=CC=1)=O.[N:37]1([CH2:44][CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]([C:55]3[C:64]4[C:59](=[CH:60][C:61]([O:65]C)=[CH:62][CH:63]=4)[CH:58]=[CH:57][C:56]=3[C:67]3[CH:72]=[CH:71][C:70]([F:73])=[CH:69][C:68]=3[F:74])=[O:54])=[CH:49][CH:48]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.B(Br)(Br)Br>>[N:37]1([CH2:44][CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]([C:55]3[C:64]4[C:59](=[CH:60][C:61]([OH:65])=[CH:62][CH:63]=4)[CH:58]=[CH:57][C:56]=3[C:67]3[CH:72]=[CH:71][C:70]([F:73])=[CH:69][C:68]=3[F:74])=[O:54])=[CH:49][CH:48]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2F)ccc2cc(O)ccc12
Product: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2ccc(F)cc2F)ccc2cc(O)ccc12
Yield: 75 %

Procedure:
By the standard demethylation procedure found in the preparation of [2-(2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone, [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,4-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-methanone (1.1 g, 2.1 mmol) is demethylated with BBr3 (1.0 mL, 10.5 mmol) to afford crude product. Purify on silica gel (0% to 5% methanol in methylene chloride) to yield 790 mg (75%) of the title compound: mass spectrum (ion spray) m/z=502.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[N:19]=[C:18]([C:20]([O:22]C)=O)[C:17](=[O:24])[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[C:15]=3[CH3:35])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>C(#N)C.C(O)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[N:19]=[C:18]([C:20]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:22])[C:17](=[O:24])[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=4)[C:15]=3[CH3:35])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NC1CC1
Reactant: COC(=O)c1nc(-c2ccnn2-c2ccc(C#N)nc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CC#N
Solvent: CCO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)nc2)nc(C(=O)NC2CC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 36.6 %

Procedure:
Methyl 6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.026 g, 0.054 mmol) in acetonitrile (0.33 ml) and ethanol (0.074 ml) were placed in a vial. Cyclopropylamine (0.14 ml, 2.0 mmol) was added, the vial sealed and stirred at 60° C. for 10 h. After evaporation, the residue was purified by preparative HPLC to give 0.010 g (37%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@H:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH2:49][CH3:50].COC(C)(C)C>CN(C)C=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][CH:34]([N:37]([CH2:49][CH3:50])[S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCN(C1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 150 mg (0.227 mmol) (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide in 1 ml dimethylformamide were added 14 mg (0.35 mmol) sodium hydride (60% dispersion in mineral oil). After stirring at room temperature for 30 min. 22 mg (0.27 mmol) iodoethane were added. The reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml tert-butyl methyl ether and washing with 20 ml water and with 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 86 mg (55%) of the title compound as an off-white foam.
Reaction SMILES: [O:1]1[C:7]2[C:2]1=C(C)C(O)=CC=2.[CH2:10]([O:12][C:13](=[O:15])[CH3:14])[CH3:11]>>[CH3:11][CH:10]([O:12][C:13]([CH3:14])=[O:15])[CH2:2][O:1][CH3:7]
Reactant: CCOC(C)=O
Reactant: Cc1c(O)ccc2c1O2
Product: COCC(C)OC(C)=O

Procedure:
An epoxy cresol novolac resin (ECN 1299) was dissolved in a 75:25 solvent solution of ethylacetate:PGMEA to obtain a reaction mixture having a solids content of approximately 20% by weight. Equimolar amounts of 4-hydroxybenzoic acid were added to the reaction mixture. BTEAC was added to the mixture (2% by weight, based upon the weight of epoxy cresol novolac resin), and the reaction mixture was heated to 120° C. in an oil bath under a nitrogen atmosphere for twenty-four hours. The reaction mixture was cooled and formulated into an anti-reflective coating (at a solids content of approximately 5% by weight) by the addition of trimethylolpropane trivinylether (crosslinking agent, obtained from Aldrich Chemical Company) and p-TSA as the catalyst for crosslinking at a temperature of 205° C. Tables 5 and 6 set forth the respective formulations of the mother liquor and anti-reflective coating compositions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[OH:14])[CH:6]=[CH:7][CH:8]=1.[Cr](Cl)(O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCC2O)c1
Agent: O=[Cr](=O)(O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C2CCCC2=O)c1
Reaction time: 1.5 h
Yield: 69131.8 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-cyclopentanol (6.4 g, 0.033 mmoles) in 140 ml of methylene chloride, add a mixture of pyridine chlorochromate (14.4 g, 0.066 mmoles), and silica gel (14.4 g). After 1.5 hours, an equivalent amount of oxidizing agent and silica gel is added and the reaction is stirred an additional 3.5 hours. Reduce the solvent in half in vacuo at 35° C. and chromatograph on silica with 3-1 hexanes-ethyl acetate to yield 4.34 g of the titled compound. 1H NMR (CDCl3): 7.25 (m, 1H), 6.81-6.74 (m, 3H), 3.8 (s, 3H), 3.31 (m, 1H), 2.5 (m, 2H), 2.3 (m, 1H), 2.1 (m, 2H), 1.9 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].C[O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](Cl)=[O:35])[CH:29]=1.N1C=CC=CC=1>C(Cl)Cl>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([CH2:9][C@@H:8]([NH:22][C:34](=[O:35])[C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([OH:37])=[O:26])[CH2:7][C@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:24])[CH3:23])=[CH:15][CH:14]=1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (70 mg, 0.201 mmol) and 3-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 mL) is added pyridine (0.5 mL) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1M HCl and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid. Next, to a solution of N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (1.2 mL, 1.12 mmol) and the mixture is stirred at 50-60° C. for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1M HCl and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1.05 minutes (condition A); MS 432.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07 Hz, 3H), 1.60 (m, 1H), 1.89 (m, 1H), 2.47 (m, 1H), 2.86 (m, 2H), 4.27 (m, 1H), 7.27-7.35 (m, 3H), 7.34 (t, 1H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01-8.07 (m, 2H), 8.39 (s, 1H), 8.47 (d, J=8.46 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=[CH:16]4)[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1.O1CCOCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>[CH3:24][NH:23][C:18]1[N:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:7]3[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]4[C:6]=3[CH:5]=[CH:4][N:3]=[C:2]4[NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:34])([F:35])[F:25])[CH:28]=3)[CH:14]=2)[N:19]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(Cl)nccc34)ccc2n1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(C(F)(F)F)c5)nccc34)ccc2n1
Temperature: 150 °C
Yield: 51.4 %

Procedure:
6-(1-Chloro-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine (8.50 g, 25.4 mmol), 3-(trifluoromethyl)benzenamine (4.30 g, 26.7 mmol), Davephos (0.40 g, 1.02 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.465 g, 0.508 mmol) were equally divided into 6 and added to 6 clear microwave vials along with 10 mL of dioxane in each vial. Nitrogen was bubbled into each vial for 10 min and lithium bis(trimethylsilyl)amide (1.0 M in THF) (50.8 mL, 50.8 mmol) divided into 6 (8.46 mL each) was added to the vials. The vials were then capped and heated to 150° C. in a Personal Chemistry Smith Synthesizer for 10 min. The reaction mixtures were combined and diluted with ethyl acetate. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20 to 100% EtOAc in hexanes and recrystallization from 3:1 ether/ethyl acetate to give N-methyl-6-(6-methyl-1-(3-(trifluoromethyl)phenylamino)isoquinolin-5-yl)quinazolin-2-amine (6.0 g, 51%) as a white solid. MS (M+H)+ 460.
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[CH:24]=[CH:23][C:10]([CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:9][CH:8]=1)([CH3:6])=[O:5])#[N:2].NCCN.O1CCCC1.C(O)C>C(#N)C>[C:1]([N:3]=[S:4]([C:7]1[CH:24]=[CH:23][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1)([CH3:6])=[O:5])#[N:2]
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Solvent: NCCN
Solvent: CCO
Solvent: CC#N
Product: CS(=O)(=NC#N)c1ccc(CN)cc1
Temperature: 60 °C

Procedure:
A solution of 2-(4-(N-cyano-S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 6c, 684 mg, 2.02 mmol) and 1,2-diaminoethane (243 μL, 219 mg, 3.64 mmol) in a mixture of acetonitrile (8 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) is heated at 60° C. for 5 h. All volatiles are removed under reduced pressure and the residue is suspended in dichloromethane. The mixture is filtered and the filtrate is concentrated under reduced pressure. Yield: 326 mg (77% of theory); ESI mass spectrum: [M+H]+=210; r.t. HPLC: 0.223 min (V001_007).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:31](C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:31][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 257.9 %

Procedure:
A mixture of 4 g (21 mmol) of the preceeding diamine, 4.6 g (21 mmol) of di-tert-butyl dicarbonate, and 100 mL of dry CH2Cl2 was stirred for 12 hours at room temperature. Solvent and volatile by-products were removed by evaporation under reduced pressure, leaving 6 g (100% yield) of 6-(tert-butyloxycarbonylamino)-1-diethylamino-2-hydroxyhexane as an oil which was not further purified. It was dissolved in 100 mL of dry tetrahydrofuran (THF) along with 3.27 g (22 mmol) of phthalimide, 5.77 g (22 mmol) of triphenylphosphine, and 3.83 g (22 mmol) of diethyl azodicarboxylate (DEAD). The solution was stirred at room temperature for 12 hours at which point, to complete the reaction, an additional 1.64 g (11 mmol) of phthalimide and 1.92 g (11 mmol) of DEAD were added and stirring continued for 1 hour. Solvent was removed and the residual oil partitioned between ether and 1% hydrochloric acid. The aqueous phase was separated, made basic with NaOH solution, and extracted with ether. The ether extract was dried over anhydrous MgSO4, filtered evaporated. A pale yellow oil resulted which was dried under high vacuum to afford 9.2 g of the protected amino-phthalimide as a pale yellow oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc(C2CCN(CC3CCNCC3)CC2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl acetate saturated with gaseous HCl (50 ml) was added to a solution of 1-[1-tert-butoxycarbonyl(4-piperidinylmethyl)]-4-(4-pyridyl)piperidine (1.65 g) in ethyl acetate (15 ml) and the resulting suspension stirred at ambient temperature for 2 hours. Solvent was evaporated to give 1-(4-piperidinylmethyl)4-(4-pyridyl)piperidine hydrochloride (1.70 g) as a yellow hygroscopic foam: NMR (d6-DMSO): 1.40 (m, 2H), 2.00 (m, 4H). 2.20 (m, 1H), 2.40 (m, 1H), 2.80 (m, 2H), 3.00 (m, 4H), 3.20 (m, 4H), 3.60 (d, 2H), 7.85 (d, 2H), 8.80 (d, 2H): m/z 260 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6](=[C:9]2C(=O)O[C:12](C)(C)[O:11][C:10]2=[O:18])[NH:7][CH:8]=1>O1CCOCC1>[CH3:12][O:11][C:10](=[O:18])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([Br:2])=[CH:8][N:7]=1
Reactant: CC1(C)OC(=O)C(=C2C=CC(Br)=CN2)C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Concentrated hydrochloric acid (10 mL) was added to a solution of 5-(5-bromo-1H-2-pyridinylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (Example 44-(1); 4.53 g, 15.09 mmol) in dioxane (20 mL), and the mixture was stirred at 100° C. for one hour. After cooling, the reaction mixture was concentrated. The residue was dissolved in methanol (20 mL) and toluene (20 mL). Trimethylsilyldiazomethane (2 M solution in diethyl ether, 25 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture to terminate the reaction. Then, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70, 40 minutes) to give the target compound as a colorless oil (2.50 g, 72%).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[C:22](O)(C(F)(F)F)=O>CO.C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:18][CH3:22])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COC(C)(C)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Yield: 179.2 %

Procedure:
A solution of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 120 mg, 0.346 mmol) and TFA (0.013 mL, 0.173 mmol) in methanol (2 mL) was stirred at rt over a weekend. The mixture was diluted with DCM, washed with 1 M aqueous sodium hydroxide and water, dried and concentrated. The residue was combined with that from another reaction done with 20 mg of Intermediate 73-2, and purified by column chromatography (eluting with hexane-EtOAc) to provide 4-bromo-7-(2-methoxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (112 mg, 77%). 1H NMR (400 MHz, chloroform-d) δ 10.53 (1H, br. s.), 8.68 (1H, d, J=8.36 Hz), 7.59 (1H, d, J=1.10 Hz), 7.36-7.44 (3H, m), 3.13 (3H, s), 1.64 (6H, s). Mass spectrum m/z 361, 363 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.C([O-])(=O)C.[Na+].CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C.CO>[N:2]1([CH:3]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH:27]=[CH:31][CH:30]=[CH:29]1
Reactant: COC1CCC(OC)O1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(n1cccc1)c1ccccc1-2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a suspension of 1.4 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 25 ml of acetic acid are added 0.41 g of anhydrous sodium acetate and 0.66 g of 2,5-dimethoxytetrahydrofuran. The mixture is stirred at boiling for 1 hour 30 minutes and, after cooling to 20° C., the solid formed is isolated by filtration, washed twice with 30 ml in total of distilled water and air-dried. The product obtained (2.45 g) is chromatographed on 25 g of neutral silica gel (0.06-0.20 mm) contained in a column 2.4 cm in diameter, eluting with a dichloromethane/methanol mixture (90/10 by volume) and collecting an 18 ml fraction and a 540 ml fraction. After addition of decolorizing charcoal, the latter fraction is filtered and the filtrate is concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 40° C. The product obtained is suspended for 10 minutes in 5 ml of methanol and then isolated by filtration, washed with 1 ml of methanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.6 g of 10-(1-pyrrolyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 6.12 (t, J=2 Hz, 2H: --H 3 and --H 4 of the pyrrole); 6.61 (s, 1H: --CH-- 10); 6.91 (t, J=2 Hz, 2H: --H 2 and --H 5 of the pyrrole); 7.08 and 7.34 (2 broad s, 1H each: --H of the imidazole); from 7.30 to 7.55 and 7.93 [mt and d respectively (J=7.5 Hz), 3H and 1H: --H 6, --H 7, --H 8 and --H 9]; 12.60 (broad s, 1H: --CONH--)).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11]C(=O)C)[C:7]([C:15]2[N:19]3[N:20]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].Cl.C>>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][OH:11])[C:7]([C:15]2[N:19]3[N:20]=[C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N3CCN(C)CC3)nn12
Agent: Cl
Product: CN1CCN(c2ccc3nnc(-c4ncc([N+](=O)[O-])n4CCO)n3n2)CC1
Reaction time: 0.5 h

Procedure:
1.8 g. 3-(5-nitro-1-β-acetoxyethyl-2-imidazolyl)-6-(4-methyl-1 -piperazinyl)-s-triazolo[4,3-b]pyridazine (obtained according to Example 23) was reacted for 1.5 hours at 50° C. with 36 ml. 2N hydrochloric acid. The solution was then treated with charcoal, evaporated in a vacuum and the residue dissolved in 10 ml. water, adjusted to about pH 9 with concentrated aqueous ammonia, left to stand for about 30 minutes and the precipitated crystals were filtered off with suction and washed with water and ether. There was thus obtained 1.1 g. of the desired 3-(5-nitro- 1-β-hydroxyethyl-2-imidazolyl)-6-(4-methyl-1-piperazinyl)-s-triazolo[ 4,3-b]pyridazine. After drying for 1.5 days in a vacuum at 70°C., the product has a melting point of 98° - 100° C. (foams up).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:19]1([C:22]2[C:27]([C:28](O)=[O:29])=[CH:26][N:25]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:23]=2)[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:28]([C:27]2[C:22]([CH:19]3[CH2:21][CH2:20]3)=[N:23][C:24]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)=[N:25][CH:26]=2)=[O:29])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 84A]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[4-(2-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.