Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[CH:4][N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=1.C([O-])(=O)C.[K+].O>CN1CCCC1=O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=2)[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: Fc1cn2ccccc2c1Br
Reactant: COCOc1cc(I)ccc1C(=O)OC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COCOc1cc(-c2c(F)c(Br)c3ccccn23)ccc1C(=O)OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
To a solution of 1-bromo-2-fluoroindolizine (0.30 g) in N-methylpyrrolidone (6.0 mL) were added methyl 4-iodo-2-methoxymethoxybenzoate (0.54 g), dichlorobis (triphenylphosphine) palladium (II) (0.05 g), potassium acetate (0.27 g) and water (0.05 mL), and the mixture was stirred at 100° C. for 5 hours. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give methyl 4-(1-bromo-2-fluoroindolizine-3-yl)-2-methoxymethoxybenzoate (0.39 g). To a solution of the obtained compound (0.39 g) in N-methylpyrrolidone (3 mL) were added zinc cyanide (0.44 g) and tetrakis (triphenylphosphine) palladium (0.22 g), and stirred at 150° C. for 1 hour using microwave reactor. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 4-(1-cyano-2-fluoroindolizine-3-yl)-2-methoxymethoxybenzoate (0.07 g). To a mixed solution of the obtained compound (0.07 g) in tetrahydrofuran (3.0 mL), ethanol (1.0 mL) and water (1.0 mL) was added lithium hydroxide monohydrate (0.04 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (1.0 mL), and the mixture was stirred at 50° C. overnight. After cooling to room temperature, to the reaction mixture was added water. The precipitated solid was collected by filtration, washed with water and methanol, and dried under reduced pressure at 50° C. to give the title compound (0.05 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]([O-:14])(=O)[CH3:12].[Na+].Cl[C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[C:24]([OH:33])[CH:25]=[CH:26][C:27]=3[OH:32])[C:22](=[O:34])[C:21]=2[C:20](Cl)=[CH:19][CH:18]=1>Cl>[OH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17]2[C:30]3[C:29](=[O:31])[C:28]4[C:23](=[C:24]([OH:33])[CH:25]=[CH:26][C:27]=4[OH:32])[C:22](=[O:34])[C:21]=3[C:20]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:12][CH2:11][OH:14])=[CH:4][CH:3]=3)=[CH:19][CH:18]=2)=[CH:3][CH:4]=1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(Cl)ccc(Cl)c21
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Agent: [Na+]
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(Nc3ccc(CCO)cc3)ccc(Nc3ccc(CCO)cc3)c21
Temperature: 120 °C
Reaction time: 4 h

Procedure:
100 g of 2-(4-aminopheny)-ethanol and 20 g of sodium acetate are introduced into a laboratory reaction apparatus and, at 120° C., 20 g of 1,4-dichloro-5,8-dihydroxyanthraquinone are added thereto. The reaction mixture is stirred for 4 hours at 120° C. and then poured into 1.2 litres of 2N hydrochloric acid. The precipitate is filtered off, washed with water until neutral and dried in a vacuum drying chamber.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=1)([CH3:9])[CH3:8].CI>CC(C)=O>[CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([O:18][CH3:1])=[O:17])[CH:11]=1)([CH3:9])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ccn(CC(=O)O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)Cn1ccc(C(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
Potassium carbonate (298 mg, 2.15 mmol) was added to a solution of 2-(3-isopropylpyrrol-1-yl)acetic acid (180 mg, 1.07 mmol) in acetone at 0° C. and the reaction was stirred at 0° C. for 15 min. Methyl iodide (0.13 mL, 2.15 mmol) was added at 0° C. and the mixture refluxed for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over neutral alumina by using 1-2% ethyl acetate in petroleum ether as eluent afforded methyl 2-(3-Isopropylpyrrol-1-yl)acetate (135 mg, 69%) as a liquid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C.C(O)(=O)C>[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:1][C:2]1[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][C:3]=12
Reactant: O=C1Cc2ccccc2C1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Temperature: 85 °C

Procedure:
A modified version of the method reported by Okamoto, et al. was employed. Okamoto, T. A.; Kobayashi, S. M.; Yamamoto, H. N., DE1952019, 1970. To a solution of 2-indanone (16.3 g, 123 mmol) in ethanol (80 mL) was added phenyl hydrazine (12.1 mL, 123 mmol) followed by acetic acid (12 drops) at room temperature. While stirring, the solution was warmed to reflux (oil bath at 85° C.) for 15 minutes at which point it was removed from the oil bath and allowed to cool to room temperature. Light yellow needle-like crystals precipitated from the solution. Upon cooling to room temperature, the solution was cooled to 0° C. for 30 minutes. The crystals were filtered via vacuum filtration and used without further purification.
Reaction SMILES: BrC(Br)(Br)[C:3]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([F:17])[CH:12]=[CH:13][C:14]=2[F:16])[N:9]=[C:8]([CH3:18])[CH:7]=1)=[O:4].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:3]([NH:5][C:6]2[C:15]3[C:10](=[C:11]([F:17])[CH:12]=[CH:13][C:14]=3[F:16])[N:9]=[C:8]([CH3:18])[CH:7]=2)=[O:4])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(N)cc1Cl
Reactant: Cc1cc(NC(=O)C(Br)(Br)Br)c2c(F)ccc(F)c2n1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)Nc2cc(C)nc3c(F)ccc(F)c23)cc1Cl
Yield: 5.3 %

Procedure:
Title compound (0.005 g) was prepared according to the method of Example 66 from acetamide D23 (0.118 g) and 3-chloro-4-methoxyaniline (0.039 g) but using pyridine as solvent. m/z (API+): 378 (MH+). 1H NMR δ: 2.62 (3H, s), 3.83 (1H, s), 7.13 (1H, d, J=9.0 Hz ), 7.28-7.40 (2H, m), 7.50-7.60 (1H, m), 7.74 (1H, d, J=2.6 Hz), 8.29 (1H, s), 8.86 (1H, d), 9.93 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)=[CH:4][CH:3]=1.[NH:25]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]2)[NH2:26].C(O)C.[O-]CC.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]2[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:26][N:25]2[C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=1
Reactant: NNc1ccc2c(c1)CCNC2=O
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=Cc1ccc(F)cc1)C2=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)CCC1C2=NN(c2ccc3c(c2)CCNC3=O)C1c1ccc(F)cc1
Temperature: 80 °C
Yield: 63 %

Procedure:
To ethyl 6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Preparation 16; 303 mg, 1.07 mmol) and 6-hydrazinyl-3,4-dihydroisoquinolin-1(2H)-one (240 mg, 1.3 mmol) (U.S. Pat. No. 6,432,974, Kelly et al., Aug. 13, 2002, intermediate 2) was added ethanol (8 mL) and 21% sodium ethoxide in ethanol (1.5 mL, 4 mmol) in a vial. The vial was flushed with argon and heated at 80° C. overnight with stirring. The reaction was quenched with 1M hydrogen chloride (8 mL) and diluted with water to give a precipitate. The precipitate was collected by vacuum filtration to give a yellow solid. The solid was dissolved in of dimethylformamide (3 mL) and purified by reverse phase chromatography with 45-75% acetonitrile/water to give (±)-3-(4-fluorophenyl)-2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid as a 25/75 mixture of the cis/trans-diastereomers (290 mg, 0.68 mmol, 63% yield). ES-MS m/z 430 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[C:27]1[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:27]2[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
1-t-butoxycarbonyl-4-hydroxypiperidine (408 mg, 2.03 mmol) and cesium carbonate (764 mg, 2.34 mmol) were added to a DMF solution (10 ml) of 2-chloro-5-bromopyrimidine (300 mg, 1.56 mmol), and stirred at room temperature for 14 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane:ethyl acetate=10:1) to obtain the entitled compound (268 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].C(NC(C)C)(C)C.[Li]CCCC.FC1C(F)=C(F)C=CC=1.[Li].[CH3:32][C:33]([OH:35])=O.C1C[O:39][CH2:38][CH2:37]1>O>[CH3:37][C:38]([C:33]([CH3:32])=[O:35])=[O:39].[OH:35][C:33]([C:4]1[C:5]([F:8])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[F:9])([CH3:32])[C:38](=[O:39])[CH3:37]
Reactant: CC(=O)O
Reactant: C1CCOC1
Reactant: Fc1ccc(F)c(F)c1
Agent: Fc1cccc(F)c1F
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(=O)C(C)(O)c1c(F)ccc(F)c1F
Product: CC(=O)C(C)=O
Temperature: -42.5 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 1,2,4-trifluorobenzene (29, 49.00 g, 371 mmol) and diisopropylamine (4.23 mL, 29.7 mmol) in THF (750 mL) at −70° C. was slowly added 2.5 M of n-BuLi (156.0 ml, 390 mmol) to maintain temperature between −45 to −40° C. The batch was agitated for 30 min. To another flask, a solution of 2,3-butadione (37.7 mL, 427 mmol) in THF (150 mL) was prepared and cooled to −70° C. The previously prepared lithium trifluorobenzene solution was transferred to the second flask between −70 to −45° C. The reaction was agitated for 1 hour at −55 to −45 and then quenched by adding AcOH (25.7 mL, 445 mmol) and then water (150 mL). After warmed to room temperature, the aqueous layer was separated. The aqueous solution was extracted with MTBE (200 mL×1) and the combined organic layers were washed with brine (100 mL×1). The organic layer was concentrated at 25-35° C. The residue was flashed with heptane (100 mL×1) and concentrated to dryness and give 30 (87.94 g, 90.2 wt %, 98% yield, and >99% HPLC purity) as an oil. 1H NMR (CDCl3, 400 MHz): δ 7.16 (m, 1H), 6.86 (m, 1H), 6.88 (s, 1H), 4.59 (s, 1H), 2.22 (s, 3H), 1.84 (dd, J=4.0, 2.8 Hz, 3H); 19F NMR (CDCl3, 376.6 MHz): δ −114.6 (dd, J=14.5, 1.4 Hz), −133.6 (d, J=19.9 Hz), −141.3 (dd, J=19.9, 14.5 Hz); 13C NMR (CDCl3, 100 MHz): δ 207.4, 156.4 (ddd, J=247, 6.2, 2.9 Hz), 149.4 (ddd, J=253, 15.0, 9.0 Hz), 147.5 (ddd, J=245, 14.4, 3.3 Hz), 119.4 (dd, J=17.3, 11.7 Hz), 117.0 (ddd, J=19.3, 11.1, 1.4 Hz), 116.6 (ddd, J=26.6, 6.5, 4.1 Hz), 77.9, 25.0 (dd, J=6.5, 4.9 Hz), 23.3.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[N+:17]([C:20]1[C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[C:24]([Cl:37])[CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl.Cl>[N+:17]([C:20]1[C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH:2][C@H:3]3[CH2:7][CH2:6][N:5]([CH2:8][C:9]4[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=4)[C:4]3=[O:16])(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[C:24]([Cl:37])[CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: N#Cc1cc(CN2CCC(N)C2=O)cs1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Oc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc(Oc4c(Cl)cccc4[N+](=O)[O-])cc3)C2=O)cs1
Reaction time: 18 h
Yield: 96.4 %

Procedure:
4-{3-(S)-[(4-(6-Nitro-2-chlorophenoxy)benzenesulfonyl)amino]-2-oxopyrrolidin-1-ylmethyl}thiophene-2-carbononitrile is prepared as described in EXAMPLE 125, Part C from of 4-(3-Amino-2-oxopyrrolidine-1-ylmethyl)thiophene-2-carbonitrile hydrochloride (0.36 g, 1.4 mmol), and 4-(6-Nitro-2-chlorophenoxy)-benzenesulfonyl chloride (0.63 g, 1.8 mmol) and triethyl amine (0.57 g, 5.7 mmol). After 18 hours, the solution is diluted with CH2Cl2 and 0.5 N HCl. The layers are separated; the organic layer is dried over NA2SO4, filtered and concentrated. The crude product is triturated with ether to afford the title compound (0.72 g, 1.35 mmol) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[ClH:21].[CH3:22][NH2:23].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:21].[ClH:21].[CH3:22][NH:23][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:16]1
Reactant: CN
Reactant: O=C1CCN(CCCOCCc2ccc(F)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CNC1CCN(CCCOCCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 14.7 g (52.6 mmol) of the preceding ketoamine (22.2) in 150 ml of CH2Cl2 is treated with 3.5 g (52.6 mmol) of methylamine hydrochloride and then methanol is added until dissolution is complete. After stirring for 3 h at 25° C., the mixture is cooled on an ice bath and 14.5 g (68.5 mmol) of sodium triacetoxyborohydride are added portionwise and, finally, 3 ml of acetic acid are added dropwise. Stirring is continued overnight at 25° C. The reaction mixture is poured into ice and basified to pH 12-13. The base released is extracted in the usual way to give a greenish oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]#[N:21])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC#N.Cl[Pd]Cl.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:18]=[C:13]3[C:12]([C:20]#[N:21])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3cccs3)cc12
Temperature: 90 °C
Yield: 39.1 %

Procedure:
A mixture of 8 (50.0 mg, 0.128 mmol), 2-(tributylstannyl)thiophene (88 μL, 0.276 mmol), dichlorobis(acetonitrile)palladium (II) (4.0 mg, 0.0138 mmol), tri-o-tolylphosphine (8.0 mg, 0.0276 mmol) and toluene (1.0 mL) were heated at 90° C. overnight. The mixture was separated by PTLC using ethyl acetate:hexane (3:7) as eluent to give 11 as a white solid (18.3 mg, 36%); 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=2.1 Hz, 1H), 8.28 (m, 3H), 8.16 (d, J=2.1 Hz, 1H), 7.68 (tt, J=7.5, 1.2 Hz, 1H), 7.57 (t, J=4.1 Hz, 2H), 7.37 (m, 2H), 7.13 (dd, J=5.1, 3.6 Hz, 1H).
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][CH2:25]3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)=[O:21]
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCN(Cc2ccc(F)cc2)CC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: NCC(=O)NCC1CCN(Cc2ccc(F)cc2)CC1
Yield: 46 %

Procedure:
A solution of the 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-fluorobenzyl)piperidine and piperidine (5 mL) in DMF (5 mL) was stirred at room temperature for 17 h. Concentration and column chromatography (SiO2, Et3N:CH3OH:CH2Cl2=0.5:2:8) afforded 4-{(glycylamino)methyl}-1-(4-fluorobenzyl)piperidine (453 mg, 46%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[Br:28]N1C(=O)CCC1=O>CC#N>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOC(=O)c1ncc2ccc(Oc3ccc(OC)cc3)cc2c1O
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
To mixture of 4-Hydroxy-6-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (1.837 g, 5 mmol; for preparation, see example 28b) and N-bromosuccinimide (1.079 g, 6 mmol) was added anhydrous MeCN with stirring. After ca. 10 min another portion of MeCN (3 mL) was added and stirring continued for 20 min. The mixture was then partitioned between water (100 mL) and CCl4 (100 mL). The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from EtOAc to give the title compound as white needles (1.345 g); MS-(+)-ion: M+1, 79Br/81Br=445.8 and 447.8.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[C:11]2=[N:12][C:13]([CH2:25][CH3:26])=[C:14]([CH2:23]O)[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:10]2[CH:9]=[N:8]1)[CH3:6]>>[Cl:3][CH2:23][C:14]1[C:13]([CH2:25][CH3:26])=[N:12][C:11]2[N:7]([CH2:5][CH3:6])[N:8]=[CH:9][C:10]=2[C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Reactant: O=S(Cl)Cl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To the solution of thionyl chloride (1.46 mL, 20.0 mmol) was added [1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (0.609 g, 2.0 mmol) slowly. The mixture was stirred at room temperature for about 30 mins before it was concentrated on rotavap under vacuum. DCM (5 ml) was added to the residue and concentrated on rotavap twice to afford 0.386 g (60%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH2:24]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[OH:28]>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH:24]=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(CBr)cc2c(Cl)nc(-c3ccccc3)nc21
Reactant: CCO
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1c(C=O)cc2c(Cl)nc(-c3ccccc3)nc21
Temperature: 48 °C
Reaction time: 1 h

Procedure:
A suspension of the bromide 7 (2.00 g, 4.73 mmol), Na2HPO4 (806 mg, 5.68 mmol) and NaH2PO4 (227 mg, 1.89 mmol) in DMSO (50 mL) is heated under nitrogen to 48° C. After 1 h, all solids are dissolved, and the reaction is continued for 2 h. The solution is then poured in H2O (600 mL), and the mixture is extracted with EtOAc (2×150 mL). The combined EtOAc layers are washed with H2O (3×400 mL) and brine and dried over MgSO4. Filtration and concentration yields a yellow solid, which is triturated with EtOH giving 1.06 g (2.97 mmol, 63%) of the title compound as a yellow solid. MS (ES): m/z 304.7/306.7 (33/10) [MH+-Boc-H2O+2 MeOH], 272.7/274.7 (100/32) [MH+-Boc-H2O+MeOH]. 1H NMR (200 MHz, CDCl3): δ=1.79 (s, 9H), 7.44 (s, 1H), 7.48-7.55 (m, 3H), 8.51-8.60 (m, 2H), 10.39 (s, 1H). tR (method A)=10.4 min.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O.[F:14][C:15]1[CH:38]=[CH:37][C:18]([O:19][C:20]2[C:28]3[N:27]=[C:26]([SH:29])[NH:25][C:24]=3[CH:23]=[C:22]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:21]=2)=[CH:17][CH:16]=1>C(OCC)(=O)C>[F:14][C:15]1[CH:38]=[CH:37][C:18]([O:19][C:20]2[C:28]3[N:27]=[C:26]([S:29][CH3:1])[NH:25][C:24]=3[CH:23]=[C:22]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:21]=2)=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(S)nc23)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
30 mg of potassium carbonate and 0.014 ml of methyl iodide were added to a dimethylformamide (1.0 ml) solution of 78 mg of 4-(4-fluoro-phenoxy)-6-(pyridin-3-yloxy)-1H-benzimidazole-2-thiol produced in Example 115, and the reaction liquid was stirred at 0° C. for 30 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].Cl>N1C=CC=CC=1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C#N)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(CCC#N)cc1OC
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 1 g (5.3 mmoles) of (2E)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile in 9.3 mL of pyridine and 2.8 mL of methanol there is added, little by little, 0.24 g of NaBH4 (6.3 mmol, 1.2 eq.). The reaction mixture is heated at reflux for 9 hours. After cooling to ambient temperature, the reaction mixture is added to a solution of 9 mL of hydrochloric acid 37% in 24 g of ice. The solution is extracted twice with dichloromethane. The organic phases are collected and the solvent is evaporated off under reduced pressure to yield 0.82 g of a red-brown oil which crystallises.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([OH:20])=O)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([NH2:23])=[O:20])[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)O)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C(N)=O)c12

Procedure:
To a solution of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (14.0 mg, 0.051 mmol) and 1,1′-carbonyldiimidazole (13.0 mg, 0.077 mmol) in N,N-dimethylformamide (2 ml) was added 28% ammonium hydroxide solution (0.072 ml, 0.51 mmol). After 30 minutes the reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide as gray solids. 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H); 8.33 (s, 1H); 8.25 (s, 1H); 8.06 (s, 1H); 7.61 (s, 1H); 7.29 (s, 1H); 7.15 (s, 1H); 4.07 (s, 3H); 3.87 (s, 3H). LRMS (ESI) calculated for C13K4N5O2 [M+H]−, 272.1 found 272.0.