Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]3=[C:15]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:16]=2)[N:11]=[CH:10]1.C(N(CC)CC)C.ClC1C=C(C=CC=1)C(OO)=[O:44]>ClCCl>[OH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]3=[C:15]([CH2:20][C:21]3[CH:22]=[N+:23]([O-:44])[C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:16]=2)[N:11]=[CH:10]1
Reactant: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one hydrochloride (0.050 g, 0.12 mmol) in 0.6 mL of dichloromethane was added triethylamine (0.012 g, 0.12 mmol). Upon dissolution of the suspension, 3-chloroperoxybenzoic acid (0.031 g, 0.13 mmol) was added and the mixture was stirred at rt for 15 h. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 416.1967 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.99-8.96 (m, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.79-7.76 (m, 1H), 7.65-7.59 (m, 2H), 6.91 (d, J=8.1 Hz, 1H), 4.61 (br s, 1H), 4.31 (s, 2H), 4.00 (br s, 1H), 2.50-2.40 (m, 1H), 2.41 (s, 3H), 2.26-2.21 (m, 1H), 2.06-1.98 (m, 1H), 1.98-1.82 (m, 3H), 1.58-1.40 (m, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][C:41]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CS(=O)(=O)Nc1ccc(O)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)ccc3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 85.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 2-hydroxy-5-(methylsulfonamido)phenylboronic acid (95 mg, 0.41 mmol, described at WO 2012013727 A1 20120202), sodium carbonate (52 mg, 0.49 mmols) and bis(triphenylphosphine)palladium(II) dichloride (41 mg, 0.05 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl ether) to give 102 mg (87% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:35])[CH:13]([CH2:31][C:32]([OH:34])=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[N+](=[CH2:38])=[N-]>CCOCC>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:35])[CH:13]([CH2:31][C:32]([O:34][CH3:38])=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCCCCCCCCCCCCCCCCC(CC(=O)O)C(=O)Nc1cccc2cnccc12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC(CC(=O)OC)C(=O)Nc1cccc2cnccc12

Procedure:
Commercially available N-(isoquinolin-5-yl )-2-(carboxymethyl)nonadecanoic amide was esterified with diazomethane in ether to give the title compound.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>ClCCl.O>[N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl isonipecotate (2.5 g, 15.9 mmol) in dichloromethane (80 mL) at 0° C. was treated with (BOC)2O (3.8 g, 17.3 mmol), warmed to room temperature, stirred for 2 hours, diluted with water, and extracted with dichloromethane. The combined extracts were washed sequentially with saturated sodium bicarbonate, 5% citric acid, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 258 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([CH3:13])=O>C(O)C>[Br:1][C:2]1[N:7]2[CH:10]=[C:11]([CH3:13])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Nc1cccc(Br)n1
Solvent: CCO
Product: Cc1cn2c(Br)cccc2n1
Yield: 82.3 %

Procedure:
6-Bromopyridin-2-amine (25.0 g, 144 mmol) and 1-chloroacetone (20.0 mL, 251 mmol) were dissolved in ethanol (300 mL) and the mixture was heated under reflux for 3 days. The precipitated solid was collected by filtration and dissolved in dichloromethane. The solution was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (25.0 g, yield 75%).
Reaction SMILES: C([N:3]1[CH2:21][CH2:20][C@@:10]23[C:11]4[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][C:16]=4[CH2:17][C@@H:4]1[C@@H:5]2[C@@H:6]([CH2:24][CH3:25])[C@H:7]([CH3:23])[C:8](=[O:22])[CH2:9]3)#N.[ClH:26]>>[ClH:26].[CH2:24]([C@@H:6]1[C@@H:5]2[C@:10]3([CH2:20][CH2:21][NH:3][C@@H:4]2[CH2:17][C:16]2[CH:15]=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]3=2)[CH2:9][C:8](=[O:22])[C@H:7]1[CH3:23])[CH3:25]
Reactant: CC[C@@H]1[C@H]2[C@H]3Cc4ccc(OC)cc4[C@@]2(CCN3C#N)CC(=O)[C@H]1C
Agent: Cl
Product: CC[C@@H]1[C@H]2[C@H]3Cc4ccc(OC)cc4[C@@]2(CCN3)CC(=O)[C@H]1C

Procedure:
Compound 12 (10.6 g, 32.4 mmol) and 2 N HCl (200 ml) was refluxed for 5 hours and the resulting solution evaporated to dryness. Upon coevaporation with ethanol, there was obtained 6.9 g (63%) of crystalline 15, mp>265°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[C@H:4]([CH2:56][CH:57]([CH3:59])[CH3:58])[NH:5][C:6](=[O:55])[C@@H:7]([CH2:51][C:52](=[O:54])[NH2:53])[NH:8][C:9](=[O:50])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:39][OH:40])[NH:14][C:15](=[O:38])[C@H:16]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH:17]C(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:60])[C@H:4]([CH2:56][CH:57]([CH3:58])[CH3:59])[NH:5][C:6](=[O:55])[C@@H:7]([CH2:51][C:52](=[O:54])[NH2:53])[NH:8][C:9](=[O:50])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:39][OH:40])[NH:14][C:15](=[O:38])[C@H:16]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:17]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
Nα -Benzyloxycarbonyl-L-tryptophyl-L-seryl-L-tyrosyl-D-asparaginyl-L-leucine methyl ester, 3.75 g. is dissolved in 200 ml. of absolute methanol, 375 mg. of 20% palladium-on-carbon added and the material reduced with hydrogen during 50 minutes. The catalyst is removed by filtration and the filtrate evaporated under reduced pressure; 1.83 g. The catalyst is extracted with 400 ml. of boiling methanol, separated by filtration and the filtrate evaporated to yield 1.22 g. of additional product.
Reaction SMILES: C([O-])(O)=O.[Na+].[N:6]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:15][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: Nn1ccc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of NaHCO3 (50 g, 0.7 mole) in 100 ml dichloromethane (DCM) was added a solution of 1H-indol-1-amine (36 g, 0.27 mole) in 200 ml DCM. After cooling to 0° C. with an ice bath, a solution of ethyl chloroformate (29 ml, 0.30 mole) in 50 ml DCM was added over a period of thirty minutes. After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil which was eluted on a silica gel column with DCM, via high performance liquid chromatography (HPLC) to give N-(1H-indol-1-yl) carbamic acid ethyl ester, 33.6 g (61%) as an oil. To a cold solution of N-(1H-indol-1-yl) carbamic acid ethyl ester (15 g, 0.07 mole) in 100 ml tetrahydrofuran, was added potassium t-butoxide (9 g, 0.08 mole), and the mixture stirred at 5° C. for one hour. To this was added 1-bromopropane (7.3 ml, 0.08 mole), and the mixture stirred at ambient temperature for five hours. The mixture was poured into 300 ml iced-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated, NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester as an oil, 16.5 g (91%). To a solution of N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester (16.5 g, 0.067 mole) in 35 ml ethylene glycol, was added a solution of NaOH (10 g, 0.25 mole) in 30 ml water. After stirring at 120° C. for four hours, the mixture was poured into 300 ml ice water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylamine, 9.0 g (78%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[O-:11][C:12]#[N:13].[K+]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:12]([NH2:13])=[O:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Product: C[C@@H](NC(N)=O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
(R)-1-(4-Fluorophenyl)ethanamine (5.15 g, 37.0 mmol) was taken up in HCl (2N, 40 mL) and potassium cyanate (15.01 g, 185 mmol) was added. The mixture was stirred at 80° C. for 3 h. Upon cooling to room temperature, a precipitate formed which was collected by filtration and washed with water. The solid was partitioned between water and EtOAc, and the aqueous phase extracted once more with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-1-(1-(4-fluorophenyl)ethyl)urea), without further purification. MS ESI calc'd. for C9H11FN2O [M+1]+ 183. found 183.
Reaction SMILES: [Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl.[N:12]([O-])=O.[Na+].NC(N)=O>O>[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH:6][NH2:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: NNc1cc(O)c(Cl)cc1F
Temperature: -30 °C
Reaction time: 3 h
Yield: 23.6 %

Procedure:
4-Chloro-2-fluoro-5-hydroxyaniline (32.5 g) was added to conc. hydrochloric acid (300 ml), and a solution of sodium nitrite (15.2 g) in water (20 ml) was added thereto at 0° to -5° C. The resultant mixture was stirred at 0 to 5° C. for 30 minutes, and urea was added thereto to remove excessive nitrite ion, followed by cooling to -30° C. A solution of stannous chloride (92 g) in hydrochloric acid (160 ml) was added thereto, and the mixture was stirred at 0° to -10° C. for 3 hours. The reaction mixture was filtered, and the precipitated crystals were dissolved in water, neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was treated with ether to give 4-chloro-2-fluoro-5-hydroxyphenylhydrazine (8.4 g) as crystals. The crystals were added to a solution of 2-hydroxyiminocyclohexanone morpholinoenamine (9.35 g), ethanol (90 ml) and a catalytic amount of acetic acid and heated under reflux for 3 hours. After cooling, ethanol was removed by evaporation, and water was added to the residue, followed by extraction with ethyl acetate. The extract was dried and concentrated, and the residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)hydrazonocyclohexanone oxime (8 g) as crystals. The crystals were suspended in a mixture of tetrahydrofuran (50 ml) and 15% pyridine-water (112 ml). A solution of cupric sulfate (CuSO4.5H2O) (11.2 g) in water (40 ml) was added to the suspension, which was heated under reflux for an additional 2 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of cupric sulfate, dried and concentrated. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (4 g) as crystals. M.P., 220°-221° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=O.[ClH:18].Cl.[O:20]([CH2:22][CH2:23][NH2:24])[NH2:21].N1C=CC=CC=1>C(O)C>[ClH:18].[NH2:24][CH2:23][CH2:22][O:20][N:21]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COCCCCC(=NOCCN)c1ccc([N+](=O)[O-])cc1

Procedure:
5.35 Mmol (1.27 g) of 5-methoxy-4'-nitrovalerophenone (melting point 64.5°-65.5° C.), 5.35 mmol (0.80 g) of 2-aminoxyethylamine dihydrochloride and 0.34 ml of pyridine were refluxed for 2 hours in 5 ml of absolute ethanol. After evaporating the reaction mixture to dryness in vacuo, 25 ml of water and 10 ml of 2 N sodium hydroxide solution were added and extracted with 25 and 10 ml, respectively, of methylene chloride. The extracts were dried over sodium sulphate and then evaporated to dryness in vacuo. Toluene was added another two times to the resulting base which was evaporated in vacuo. The residue was dissolved in absolute ethanol and an equimolar quantity of alcoholic hydrochloric acid was added. After the addition of diethyl ether, the title compound crystallized. Melting point 121.5°-122.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1O[C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][N:33]([CH2:35][CH2:36][NH2:37])[CH3:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:37]([CH2:36][CH2:35][N:33]([CH2:32][CH2:31][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH3:34])[C:14](=[O:16])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1
Reactant: COc1ccccc1Cc1nc2ccccc2c(=O)o1
Reactant: COc1ccc(CCN(C)CCN)cc1OC
Solvent: Cc1ccccc1C
Product: COc1ccccc1Cc1nc2ccccc2c(=O)n1CCN(C)CCc1ccc(OC)c(OC)c1
Yield: 21.9 %

Procedure:
268 mg (1 mmol) of 2-(2-methoxyphenylmethyl)-4H-3,1-benzoxazine-4-one and 238 mg (1 mmol) of 2-[[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamino]]ethyl-amine were heated in xylene (10 ml) under reflux for 10 hours . After the xylene was distilled off, the residue obtained was purified by silica gel column chromatography (eluent; 2% ethanol/chloroform) to obtain 107 mg (52%) of 2-(2-methoxyphenylmethyl)-3-[2-{N-(3,4-dimethoxyphenylethyl)-N-methylamino}ethyl]-4(3H)-quinazolinone as an oily substance. Subsequently, the thus obtained quinazolinone was dissolved in ethanol (2 ml) and to the resulting soluion there was added a 7% hydrogen chloride-ethanol solution (1 ml). Further, ether was added to the reaction mixture thus obtained, and the precipitated colorless crystals were collected by filtration to obtain 99 mg of the hydrochloride which is the desired compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([NH2:34])=[CH:29][N:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:34][C:30]3[CH:29]=[N:28][C:27]([N:26]([CH3:25])[CH3:35])=[CH:32][C:31]=3[CH3:33])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Cc1cc(N(C)C)ncc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 43.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 472 mg, 1.27 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (580 mg, 3.81 mmol) and p-toluenesulfonic acid monohydrate (241 mg, 1.27 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 135 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (266 mg, 0.547 mmol, 43%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH2:36][CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)=[O:22])(=[O:15])=[O:16])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: NCCCn1ccnc1
Product: O=C(NCCCn1ccnc1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0316 cm3 of N-(3-aminopropyl)imidazole. 54 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide are thus obtained in the form of a yellow foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.97 (mt, 2H), 2.98 (s, 3H), 3.25 (mt, 2H), 3.81 (mt, 2H), 4.02 (t, J=7 Hz, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), from 6.85 to 6.95 (mt, 2H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8 Hz, 1H), 8.56 (t, J=5.5 Hz, 1H)].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30]([CH:32]4[CH2:33][CH2:34]4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=C(CCCCCl)c1cccc([N+](=O)[O-])c1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1cccc([N+](=O)[O-])c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 450.2 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].[C].CO.O1CCCC1>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:23]1[C:9]([OH:8])=[CH:10][C:11]2[NH:15][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[N:13][C:12]=2[CH:22]=1
Reactant: [H][H]
Reactant: Fc1ccccc1Oc1cc2[nH]c(-c3cnccn3)nc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccccc1F

Procedure:
500 mg of 20% palladium hydroxide-carbon catalyst was added to a suspension of 697 mg of 5-benzyloxy-6-(2-fluorophenoxy)-2-pyrazin-2-yl-1H-benzimidazole obtained in Example 250, in 10 ml of methanol and 10 ml of tetrahydrofuran, and the reaction liquid was stirred in a hydrogen atmosphere at room temperature for 1 hour. The catalyst was removed through filtration through Celite, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: ethyl acetate) to obtain the entitled compound as a yellow solid.