Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(NC(C)C)(C)C.[C:34]([CH:36]1[CH2:38][CH2:37]1)#[CH:35]>CCOC(C)=O.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.[Cu]I>[CH:36]1([C:34]#[C:35][C:2]2[CH:15]=[CH:14][C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:9][CH:10]=4)[C@:5]4([CH2:25][O:24][C:23]([NH2:26])=[N:22]4)[C:4]=3[CH:3]=2)[CH2:38][CH2:37]1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3CC3)ccc1O2
Temperature: 50 °C

Procedure:
A vial was charged with (4R)-2′-bromo-7′-(2,2-dimethylpropoxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (52.5 mg, 126 μmol), tetrakis(triphenylphosphine)palladium(0) (14.5 mg, 12.6 μmol), copper(I) iodide (4.79 mg, 25.2 μmol), diisopropylamine (629 μl, 126 μmol), and ethynylcyclopropane (32.0 μl, 377 μmol). The vial was heated in a 50° C. oil bath for 15 h. The reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was evaporated, and the crude residue was purified by chromatography on a 12-g Redi-Sep column, eluting with 0-5% MeOH/DCM to give (4S)-2′-(cyclopropylethynyl)-7′-(2,2-dimethylpropoxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=403.2 [M+H]+. Calc'd for C25H27N2O3: 403.2.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.[Cl-].[CH2:13]([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH2+:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]3[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:22])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1ccc2oc(Cl)nc2c1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: Cc1ccc2oc(N3CCCC[C@H]3C(=O)OCc3ccccc3)nc2c1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from 2-chloro-5-methyl-1,3-benzoxazole [see J.Med.Chem, 1988, 31, 1719-1728] and (2S)-2-[(benzyloxy)carbonyl]piperidinium chloride [see EP 530167 A1 930303]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-(5-methyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Temperature: 170 °C
Yield: 64 %

Procedure:
A mixture of 5.4 g of 1,4-dichlorobenzene, 4.2 g of aluminum chloride and 0.5 ml of benzoyl chloride was stirred at 170° C. Additional benzoyl chloride, up to a total of 4 g, was slowly added to the mixture over 2.5 hours, and the resulting mixture was stirred for another hour at 170° C. The molar ratio of reactants was 1.1/1.3/ (AClCl3 :Dichlorobenzene:Benzoyl Chloride). After work-up of the crude mixture as in Examples 7 through 10, 2,5-dichlorobenzophenone was obtained in 64% yield, as determined by gas chromatography using 3-chlorobenzophenone as the internal standard.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[C:12]([Cl:16])=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[Cl:16][C:12]1[CH:11]=[C:8]([CH2:9][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]([Cl:6])=[CH:14][C:13]=1[OH:15]
Reactant: C1CCNC1
Reactant: O=Cc1cc(Cl)c(O)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cc(Cl)c(CN2CCCC2)cc1Cl
Yield: 78.3 %

Procedure:
Pyrrolidine (0.48 mL, 5.76 mmol) was added to a suspension of Intermediate 24, 2,5-Dichloro-4-hydroxybenzaldehyde (0.88 g, 4.6 mmol) in dichloromethane (10 mL). The reaction mixture was cooled with an ice bath. Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (20 mL) and dichloromethane (10 mL) were added. The reaction mixture was acidified with 5N NAHSO4 to pH˜2. The organic layer was separated. The aqueous one was subjected to extraction with CH2Cl2 (2×30 mL), and the extracts were discarded. The aqueous fraction was alkalized with a saturated solution of potassium carbonate to pH 9-10. The product was extracted with CH2Cl2 (3×20 mL). The organic layer was dried with anhydrous Na2SO4 (5 g). The solvent was evaporated in vacuo, and coevaporated with dioxane to give the title compound (0.89 g, 3.6 mmol, 79%) as pale-yellow crystals. LC/MS data: 248.0, 247.0 and 246.0 (M+H); 174.9 (M-pyrrolidine+H) (calculated for C11H13ClNO 246.1). 1H NMR data (DMSO-d6): 10.52 (br.s., 1H, OH); 7.38 (s, 1H, s Ar—H); 6.98 (s, 1H, Ar—H); 3.54 (s, 2H, CH2Ar); 2.40-2.47 (m, 4H); 1.63-1.74 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[C:11]([O:17][CH3:18])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:15]([C:12]1[N:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[CH:3]=2)=[N:10][C:11]=1[O:17][CH3:18])#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1nc(Nc2cc(Cl)ncn2)cnc1C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc(Nc2cc(NCC3CCN(C(=O)OC(C)(C)C)CC3)ncn2)cnc1C#N
Yield: 40.1 %

Procedure:
A solution of 5-(6-chloropyrimidin-4-ylamino)-3-methoxypyrazine-2-carbonitrile (4.5 mg, 0.017 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (4 mg, 0.034 mmol) and triethylamine (12 uL, 0.085 mmol) in acetonitrile (1.5 mL) was heated at 145° C. for 90 min using microwave irradiation. The solvent was removed in vacuo and the crude mixture was purified by preparative thin layer chromatography, eluting with dichloromethane/MeOH (10/1), to give the title compound as a yellow oil (3 mg, 40%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[C:22]([Cl:23])=[C:21]([C:24]#[N:25])[NH:20][C:19]=1[C:26](Cl)=[O:27]>C1COCC1>[Cl:17][C:18]1[C:22]([Cl:23])=[C:21]([C:24]#[N:25])[NH:20][C:19]=1[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=2)[CH2:4][CH2:3]1)=[O:27]
Reactant: COC(=O)c1cnc(N2CCC(N)CC2)s1
Reactant: N#Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCC(NC(=O)c3[nH]c(C#N)c(Cl)c3Cl)CC2)s1
Reaction time: 0.25 h

Procedure:
TEA (0.06 ml, 0.5 mmol) was added to a solution of methyl 2-(4-aminopiperidin-1-yl)-1,3-thiazole-5-carboxylate (Intermediate 134, 0.1 g, 0.5 mmol)) in anhydrous THF. To this was added 3,4-dichloro-5-cyano-1H-pyrrole-2-carbonyl chloride (Intermediate 132, 0.1 g, 0.5 mmol) as a solution in anhydrous THF. After stirring 15 minutes, THF was removed. The product was partitioned with EtOAc and water. The organic portion was dried with MgSO4 and concentrated to a yellow oil. Trituration with ether followed by filtration yielded a tan solid.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29]O)[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29][O:15][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Product: COC(=O)c1ccc(C(C)(C)C)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Yield: 32.1 %

Procedure:
In a manner substantially equivalent to Example 21-C, methyl 4-tert-butyl-2-hydroxybezoate (2.08 g, 10.0 mmol) and 1-Boc-3-hydroxymethylpiperidine (2.15 g, 10.0 mmol) were reacted to give the desired product (1.30 g, 32.1%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO.CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:12][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[CH3:18]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nc2ccccc2[nH]1
Yield: 92.7 %

Procedure:
A solution of 2-mercaptobenzimidazole (200 mg, 1.33 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (2.5 mL) and acetone (2 mL) was shaken at 20° C. for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (326 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.31 (br. s, 1H), 7.24 (br. s, 1H), 7.15-7.05 (m, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.29 br. s, 1H), 3.90 (br. s, 1H), 1.24 (t, J=7.1 Hz, 3H). MS (ESI): m/z 265 (M+1, 100).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]#N)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.C(OC([C:31]1C2C(=CC=CC=2)C=C[N:32]=1)(C)C)(=O)C1C=CC=CC=1>>[CH2:6]([CH:1]([C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:31]#[N:32])[C:11]=2[CH:10]=[CH:9][N:8]=1)[CH2:2][CH3:3])[CH3:5]
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Reactant: N#Cc1cccc2c(-c3ccccc3)nccc12
Product: CCC(CC)c1nccc2c(CC#N)cccc12

Procedure:
1-(1-Ethylpropyl)isoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-(1-ethylpropyl)-5-dichloroacetylaminomethylisoquinoline. The product was successively reacted in the same way as in steps (c), (d), (e) and (f) of Example 18 to afford 1-(1-ethylpropyl)-isoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-(1-ethylpropyl)-isoquinoline-5-acetic acid as an oil. The hydrochloride of the product was in the form of colorless prisms having a melting point of 107° to 109° C.
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]1)=[O:6].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[O:23]1[CH:10]2[CH:9]1[CH2:8][N:7]([C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:13])[Cl:14])=[O:6])[CH2:12][CH2:11]2
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
100 g (0.38 mol) of 1-(β,β,β-trichloroethoxycarbonyl)-1,2,5,6-tetrahydropyridine are dissolved in 1,200 ml of methylene chloride and the solution is treated with 157 g (0.77 mol) of 85% strength m-chloroperbenzoic acid in portions. The slightly exothermic reaction is kept at room temperature by means of a water bath. After the addition has ended (which takes about 2 hours), the reaction mixture, in which a white suspension forms, is stirred for a further 15 hours at room temperature. The m-chlorobenzoic acid which has precipitated is filtered off and the filtrate is washed with a saturated aqueous solution of sodium carbonate, then with aqueous iron-II sulphate solution, then with 0.1 N sodium hydroxide solution and finally with water, dried over sodium sulphate and evaporated under a water pump vacuum. The oil which remains is dissolved in 100 ml of benzene and the solution is filtered through a layer of silica gel. Elution with a benzene/ethyl acetate mixture (1:1) and evaporation of the solvent gives pure 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-piperidine in the form of a slightly orange coloured oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[N:25]([CH2:32][C:33]2([CH3:36])[CH2:35][O:34]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1>CN(C=O)C>[CH3:35][C:33]1([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:34][C:24]2=[N:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]2[CH2:32]1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
Tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (2.01 g, 7.23 mmol) was dissolved in DMF (20 ml). To the solution, sodium hydride (320 mg, 8 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 70° C. To the solution, 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (1.5 g, 7.23 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) and then crystallized from methylene chloride/ethyl acetate to afford tert-butyl 4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (1.5 g, yield 45%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=[O:25])[CH:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:26]([NH2:28])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[CH:29]1([Mg]Br)[CH2:31][CH2:30]1>C1COCC1>[CH:29]1([CH:24]([OH:25])[C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:14]3[CH:13]=[C:12]4[C:17]([C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[CH:9][C:10]([C:26]([NH2:28])=[O:27])=[N:11]4)=[CH:16][CH:15]=3)[CH:23]=2)[CH2:31][CH2:30]1
Reactant: Br[Mg]C1CC1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C=O)cn3)cc2n1
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C(O)C4CC4)cn3)cc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a 0° C. solution of 4-(4-fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carboxamide (3-9, 36.0 mg, 0.0960 mmol, 1.0 equiv.) in anhydrous THF, under nitrogen was added dropwise 0.5 M cyclopropylmagnesium bromide in THF (0.769 mL, 0.385 mmol, 4.0 equiv.). The resulting mixture was stirred at 0° C. for 1 hour, quenched with sat. aqueous NH4Cl, extracted with ethyl acetate (3×5.0 mL), dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 7-({4-[cyclopropyl(hydroxy)methyl]-1H-pyrazol-1-yl}methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-10, 25.0 mg, 62.4%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.228 (s, 1H); 8.084 (br s, 1H); 7.995 (s, 1H); 7.929 (d, J=8.81 Hz, 1H); 7.625 (s, 1 μl); 7.515 (s, 1H); 7.442-7.506 (m, 3H); 7.206-7.249 (m, 2H); 5.777 (br s, 1 μl); 5.526 (s, 2H); 4.044 (d, J=8.48 Hz, 1H); 1.185-1.258 (m, 1H); 0.599-0.638 (m, 2H); 0.331-0.454 (m, 2H). LRMS m/z (M+H)+ 417.2 found, 417.2 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[O:10][CH:11]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:5][CH:4]=1.[C:59]1(=[O:65])[O:64][C:62](=[O:63])[CH2:61][CH2:60]1>>[CH3:58][O:57][C:54]1[CH:53]=[CH:52][C:51]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:12]2[N:13]([C:18](=[O:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:14][CH:15]([O:17][C:59](=[O:65])[CH2:60][CH2:61][C:62]([OH:64])=[O:63])[CH2:16]2)=[CH:56][CH:55]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Reactant: O=C1CCC(=O)O1
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(OC(=O)CCC(=O)O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above described procedure, the amide 102e (2.4 g, 3 mmol) was treated with succinic anhydride and after work-up the amide was isolated as a foam (2.69 g, 99%) and this was used in the next step without further purification.
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]>C(O)C>[N+:18]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([O-:20])=[O:19]
Reactant: Nn1ccc2ccccc21
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 4-chloro-3-nitropyridine in ethanol at 70° C. for 3 hours in substantially the same manner as in Example 1. Recrystallized from ethanol, m.p. 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([NH:11][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])[N:3]=1.[C:19](OC(OCC)OCC)(=O)C>>[C:12]([NH:11][C:4]1[N:3]=[C:2]2[N:1]=[CH:10][N:9]([CH3:19])[C:7](=[S:8])[N:6]2[N:5]=1)([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCOC(=O)C(=O)Nc1nc(N)n(C(=S)NC)n1
Product: CCOC(=O)C(=O)Nc1nc2ncn(C)c(=S)n2n1
Yield: 78 %

Procedure:
The synthesis method of Example 55 was applied. The compound (551 mg) obtained in Example 35 and diethoxymethyl acetate (8 ml) were used as reagents. The mixture was reacted at 90° C. for 2 hours to give 442 mg of white powdery crystals (yield 78%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)C1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)C3CCCC3)cc2n1
Yield: 10 %

Procedure:
As described for Example 47, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) was converted, using cyclopentanecarboxylic acid instead of 3-pyridylacetic acid, to the title compound (11.1 mg, 10%) which was obtained as an off-white solid. MS: m/e=387.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][NH:29]1>>[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][N:29]1[C:18]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:6]3[CH:5]=[C:4]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[N:3]=[C:2]([NH2:1])[N:7]=3)[CH2:9]2)=[CH:14][CH:13]=1)=[O:19]
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Reactant: c1ccc2c(c1)CNC2
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)N5Cc6ccccc6C5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and isoindoline (Aldrich Cat. No. 515574). LCMS (M+H)+: m/z=470.2.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:15]2[C:16]3[CH2:17][CH:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:10][C:11](=[O:18])[C:12]=3[CH:13]=[CH:14]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CC(c2ccccc2)CC3=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a suspension of 60% sodium hydride (0.16 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added p-toluene sulfonylchloride (0.76 g), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 1-(4-methylphenyl)sulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[Cl:1][C:2]1[C:3]2[O:10][C@@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][C@@H:12]3[CH2:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: OCc1cccc(Cl)c1O
Reactant: C1=Cc2ccccc2C1
Product: Clc1cccc2c1O[C@@H]1c3ccccc3C[C@@H]1C2

Procedure:
3-Chloro-2-hydroxybenzyl alcohol (20.0 g) (prepared by the method of Zincke, Hanus and Ziegler, J.Prakt. Chem., (2), 152 126(1939)), and indene (15 ml) were heated together at 190°-200° for 2.5 hr. The crude product was chromatographed on silica gel, eluting with toluene/60°-80° petroleum ether to yield a colourless oil (2.34 g) which was distilled in vacuo to give an oil which crystallised on standing (1.70 g., b.pt. 115°-120°/0.05 mmHg m.pt. 60°-63°). The recrystallised product, from ethanol was identified, by 1H-n.m.r., as cis-6-chloro-4b,10,10a,11-tetrahydrobenz(b)indeno(2,1-e) pyran, (1.20 g., m.pt-63°-65°).