Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:13][C:14]1[CH:32]=[CH:31][C:17]([CH:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C(O)=O.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:28]1[CH2:27][CH2:26][N:25]([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:32][CH:31]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(CN2CCN(C(c3ccccc3)c3ccc(F)cc3)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
2,4-Dimethoxybenzaldehyde (6.65 g; 40.0 millimoles) and 10.8 g (39.9 millimoles) of 4-fluorobenzhydrylpiperazine (see German OLS 1929330) were melted in an oil bath at 120° C., and 2.3 ml (61.0 millimoles) of formic acid was added dropwise. The mixture was stirred for 1 hour under heat, and then allowed to cool to room temperature. Then, 50 ml of an ethanol solution containing 5.0 g (43.1 millimoles) of fumaric acid was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 6.5 g (yield 30.4%) of 1-(2,4-dimethoxybenzyl)-4-(4-fluorobenzhydryl)piperazine fumarate as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].COC1C=C(C=CC=1[N+]([O-])=O)C(O)=O>[Pd].C(OCC)(=O)C>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Agent: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(F)c1

Procedure:
150 mg of 10% palladium on charcoal was added to a solution of the above mixture consisting of methyl 3-fluoro-4-nitrobenzoate and 3-methoxy-4-nitrobenzoic acid (1.7 g) in 50 mL ethyl acetate and maintained under H2 (45 psi) for two hours. The reaction mixture was filtered over Celite and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 10% methanol/dichloromethane), giving 0.7 g of methyl 4-amino-3-fluorobenzoate as an off-white solid.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:42]=[CH:41][CH:40]=[CH:39][C:15]=2[C:16]([NH:18][C:19]2[CH:35]=[C:34]([N+:36]([O-])=O)[CH:33]=[CH:32][C:20]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[O:22])=[O:17])=[O:9])[S:6][CH:7]=1.[BH4-].[Na+].[CH3:45][OH:46]>C1COCC1.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[NH2:36][C:34]1[CH:33]=[CH:32][C:20]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[O:22])=[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:39]=[CH:40][C:41]([O:46][CH3:45])=[CH:42][C:14]=2[O:13][CH2:12][CH2:11][NH:10][C:8]([C:5]2[S:6][CH:7]=[CH:3][CH:4]=2)=[O:9])[CH:35]=1
Reactant: CO
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccccc2OCCNC(=O)c2cc(OC)cs2)cc1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(OC)cc2OCCNC(=O)c2cccs2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The 2-[2-[4-methoxy-2-(thiophen-2-ylcarbonylamino)ethoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (258 mg, 0.44 mmol) was diluted with methanol (20 mL) and THF (20 mL). Nickel acetate tetrahydrate (220 mg, 0.88 mmol) was added and the mixture was cooled to 0° C. Sodium borohydride (72 mg, 1.90 mmol) was then added in portions. Vigorous bubbling occurred and the reaction turned black. After 15 minutes, the reaction was concentrated in vacuo. The crude residue was diluted with EtOAc (60 mL), water (20 mL), and concentrated ammonium hydroxide (10 mL). The resulting mixture was stirred for 5 minutes and then it was poured into a separatory funnel and the layers were separated. The organic layer was washed with water (20 mL) and brine (20 mL) and then dried over magnesium sulfate, filtered and concentrated to give the desired product (201 mg, 0.36 mmol, 81%) as a grey solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([I:19])=[C:13]([CH:18]=1)[C:14]([NH:16][OH:17])=[NH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=O)[CH3:23]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([I:19])=[C:13]([C:14]2[N:15]=[C:22]([CH3:23])[O:17][N:16]=2)[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(I)c(C(=N)NO)cc1OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(I)c(-c2noc(C)n2)cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-benzyloxy-N-hydroxy-2-iodo-4-methoxy-benzamidine (reference example 3-3) (20 g) and pyridine (115 mL) was added acetyl chloride (3.8 mL) under ice-bath cooling. After stirring at the same temperature for 3 hours, the mixture was stirred and heated at 120° C. for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and 2 mol/L hydrochloric acid. The separated organic layer was washed with 2 mol/L hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 15%-50% ethyl acetate/hexane, gradient elution) to give the title compound (17.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:23])[NH:11][CH:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Cl)[CH:34]=1.CCOC(C)=O.CCCCCC>CN(C)C=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:23])[N:11]([CH:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:13]([CH3:15])[CH3:14])[CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[CH:6][CH:5]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1ccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2cccnc2)C(C(=O)OC(C)(C)C)C(C)C)cc1

Procedure:
To a stirring solution of 4-(1-tert-Butoxycarbonyl-2-methyl-propylsulfamoyl)-benzoic acid methyl ester (Compound 1*—884 mg, 2.38 mmol) in dimethylformamide (30 ml) at ambient temperature was added cesium carbonate (10.86 g, 33.34 mmol). Then 3-picolyl chloride hydrochloride (546 mg, 3.33 mmol) was added to the suspension and the reaction mixture was stirred at room temperature for 24 hours by which time TLC (EtOAc/Hexane 1:1) monitoring showed the reaction to be completed. The mixture was evaporated to dryness and the residue was stirred in ethyl acetate (50 ml). The ethyl acetate phase was extracted with water (1×50 ml), dried (MgSO4), filtered and evaporated to afford the crude product as a brown oil. This oil was purified by flash chromatography to furnish the pure product as colourless oil.
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH:13]C(=O)C)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-:3])=[O:2]>Cl.O>[N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCC2
Agent: Cl
Solvent: O
Product: Nc1ccc2c(c1[N+](=O)[O-])CCC2
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A suspension of N-(4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (0.90 g, 4.09 mmol) in 5 M HCl was heated at 100° C. for 16 h. The suspension was cooled to 20° C., diluted with water (100 mL), filtered, washed with water (3×15 mL) and dried to give 4-nitro-5-indanamine 3 (Schroeder, E, et al., European J. Med. Chem. 1982, 17, 35) (0.69 g, 95%) as an orange solid: mp (H2O) 105-107° C.; 1H NMR δ 7.17 (d, J=8.2 Hz, 1H, H-7), 6.62 (d, J=8.2 Hz, 1H, H-6), 5.73 (br s, 2H, NH2), 3.32 (br t, J=7.5 Hz, 2H, H-3), 2.80-2.85 (m, 2H, H-1), 2.02-2.11 (m, 2H, H-2). Anal. calcd for C9H10N2O2: C, 60.7; H, 5.7; N, 15.7. Found: C, 60.5; H, 5.5; N, 15.8%.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[OH-:20].[Na+].Cl>O>[OH:20][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1-c1cn(C)c2cc(O)ccc2c1=O
Temperature: 25 °C

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5 g) and aqueous sodium hydroxide (5N, 80 ml) was stirred and boiled under reflux for 45 hours. Water (180 ml) was added to the mixture which was then cooled to ambient temperature. The solution was acidified with concentrated hydrochloric acid to pH 4. The resulting precipitate was collected by filtration and washed with boiling industrial methylated spirit (300 ml) and then hot butanol (120 ml). The residue was crystallised from 50% aqueous industrial methylated spirit to give the novel compound 7-hydroxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. >320°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].N[C@H](C(O)=O)[CH2:12][CH2:13][C:14](O)=[O:15]>>[C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:15])[CH:13]=[CH2:12]
Reactant: NCCCCCC(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: C=CC(=O)NCCCCCC(=O)O
Yield: 85 %

Procedure:
Using the same procedure as previously described except substituting 6-aminocaproic acid for the glutamic acid, the crude product was obtained in greater than 85% yield. After crystallization from water or ethyl acetate, the white, crystalline N-acryloyl-6-aminocaproic acid had a melting point of 88°-90° C.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:24][OH:25])[NH:20][CH:21]2[CH2:23][CH2:22]2)=[C:15](F)[CH:14]=1>O1CCCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[C:19]([NH:20][CH:21]3[CH2:23][CH2:22]3)=[N:24][O:25][C:15]=2[CH:14]=1
Reactant: ON=C(NC1CC1)c1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Brc1ccc2c(NC3CC3)noc2c1
Yield: 70.1 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.12 ml) was added to 4-bromo-N-cyclopropyl-2-fluoro-N′-hydroxybenzenecarboximidamide (Intermediate 52) (0.2 g) in tetrahydrofuran (2 ml) then heated at 150° in a microwave for 70 min. The mixture was applied to a Varian Bond-Elut SPE cartridge (silica, 20 g) then eluted with cyclohexane:ethyl acetate (100:0 to 80:20) to give the title compound as a white solid (0.13 g).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:25][CH2:24][C@@:13]34[C:14]5[CH:15]=[C:16]([O:21][CH2:22][CH3:23])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4)=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.[OH-].[Na+]>[CH:1]1([CH2:4][N:6]2[CH2:25][CH2:24][C@@:13]34[C:14]5[CH:15]=[C:16]([O:21][CH2:22][CH3:23])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4)[CH2:2][CH2:3]1
Reactant: CCOc1ccc2c(c1)[C@]13CCN(C(=O)C4CC4)[C@H](C2)[C@@H]1CCOC3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1CCOC3

Procedure:
The product of Step (c) (XXXIII) (0.005 m) in tetrahydrofuran (20 ml) is added to a suspension of lithium aluminum hydride (0.57 g) in tetrahydrofuran (20 ml), and the mixture is heated at reflux for 18 hours. The mixture is then cooled and saturated sodium sulfate solution (1.8 ml) and a few drops of dilute sodium hydroxide are cautiously added. The mixture is warmed until the solids are completely white. Solid sodium sulfate is added, the solids are removed by filtration and washed well with ethyl acetate. Concentration of the combined filtrate and washes gives the title product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:32][CH:33]([CH3:35])[CH3:34])[S:18]([C:21]2[CH:22]=[CH:23][C:24](O)=[C:25]([CH:30]=2)[C:26]([O:28][CH3:29])=[O:27])(=[O:20])=[O:19])=[CH:13][CH:12]=1)[CH3:10].C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:32][CH:33]([CH3:34])[CH3:35])[S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[C:25]([CH:30]=2)[C:26]([O:28][CH3:29])=[O:27])(=[O:20])=[O:19])=[CH:13][CH:12]=1)[CH3:10]
Reactant: OCC1CCOCC1
Reactant: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)c(C(=O)OC)c2)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(C(=O)OC)c2)cc1
Reaction time: 1 h

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (74.2 mg, 0.639 mmol) and methyl 5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-hydroxybenzoate (500 mg, 1.277 mmol) in toluene (0.5 mL) at room temperature, was added a solution of 2-(tributylphosphoranylidene)acetonitrile (339 mg, 1.405 mmol) in toluene (0.5 mL) in one charge. The reaction mixture was stirred vigorously for 1 hour, then left to stand overnight. Additional 2-(tributylphosphoranylidene)acetonitrile (339 mg, 1.405 mmol) and (tetrahydro-2H-pyran-4-yl)methanol (74.2 mg, 0.639 mmol) were added and the reaction mixture stirred for an additional 8 hours. The solvent was evaporated in vacuo to give the crude product, which was purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane) to give the title compound as an orange gum, 109.6 mg. LCMS [LCMS1] Rt 1.37 min, m/z (ES+) 490 (M+H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[N:12]1[C:16](=[O:17])[CH2:15][C:14]([NH:18][C:19](=[O:21])[CH3:20])=[N:13]1.O>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[N:12]1[C:16](=[O:17])[CH:15]([Br:1])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[N:13]1
Reactant: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br
Reaction time: 1 h
Yield: 83.9 %

Procedure:
27.2 g (0.17 mol) of bromine were slowly added dropwise to a solution of 54.5 g (0.17 mol) of 1-(2,4,6-trichlorophenyl)-3 -acetylamino-5-oxo-2-pyrazoline in 300 ml of acetic acid, followed by stirring for 1 hour. The reaction mixture was then added to 900 ml of water, and the deposited crystals were filtered to obtain 57 g (84%) of 1-(2,4,6-trichlorophenyl)-3-acetylamino-4-bromo-5-oxo-2-pyrazoline.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Yield: 89 %

Procedure:
The intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (1.01 g, 3.5 mmol) was reacted with 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline (1.0 g, 3.5 mmol) from Example 21A Step 5 as described in Example 46 to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea (1.69 g, 3.12 mmol, 89%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 7.36 (s, 2H), 7.28 (d, 1H), 6.49 (s, 1H), 4.31 (t, 2H), 4.00 (s, 3H), 3.85 (t, 2H), 2.37-2.25 (m, 2H), 1.29 (s, 9H); LC-MS (ESI) m/z 542 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:8]([Cl:9])=[C:7]([CH:10]([CH3:12])[CH3:11])[NH:6][N:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH:10]([C:7]1[C:8]([Cl:9])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])[N:6]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1n[nH]c(C(C)C)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C(C)C)c1Cl

Procedure:
Protocol T was followed using 3,5-Diisopropyl-4-chloro-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1, Rf=0.76) afforded the title compound as white solid. MS (ES) M+H) expected=406.9, found 407.1.
Reaction SMILES: [Mg].BrC(Br)C.[CH:6]([O:8][CH2:9][CH2:10]CCl)=[CH2:7].[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[C:14]1=[O:23])[CH2:20]2>O.OS(O)(=O)=O.C1COCC1>[CH:6]([O:8][CH2:9][CH2:10][C:14]1([OH:23])[CH:15]2[CH2:21][CH:19]3[CH2:18][CH:17]([CH2:22][CH:13]1[CH2:20]3)[CH2:16]2)=[CH2:7]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: C=COCCCCl
Agent: CC(Br)Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=COCCC1(O)C2CC3CC(C2)CC1C3

Procedure:
(Step-2) Magnesium metal(2.6 g) and anhydrous tetrahydrofuran (hereinafter referred to as THF(100 mL)) were added to a round bottom flask. Next, after dripping a small quantity of dibromoethane into the round bottom flask containing the resulting mixture to promote the reaction, 3-chloropropyl vinyl ether (12 g, 0.1 mol) and anhydrous THF(100 mL) were added drop-wise thereto. Then, the mixture was reacted for 2 hours. After dripping an adequate quantity of THF containing 2-adamantanone (15 g, 0.1 mol) in the mixture, the resulting mixture was refluxed for 12 hours. After the reaction was completed, the reaction mixture was slowly dissolved in excessive water and neutralized with thin H2SO4 solution. Then, the organic layer was extracted from the reaction solution using an adequate quantity of diethyl ether and then dried with anhydrous sodium sulfate. Next, after evaporating the solvent to obtain an oily residue using a rotary evaporator, the product was separated using a column chromatography method (hexane:ethyl acetate=3:1). (Yield: 60%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(O)c([N+](=O)[O-])c3)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCOCC4)c([N+](=O)[O-])c3)nc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
4-(6-Chloro-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-nitrophenol (Example 248) (105 mg, 0.34 mmol), 4-(2-chloroethyl)morpholine hydrochloride (74 mg, 0.40 mmol) and sodium hydride (29 mg, 1.2 mmol) were dissolved in DMF (13 ml). The reaction mixture was stirred at 100° C. overnight and then quenched with water (5 ml) and evaporated. The residue was dissolved in CH3CN (4 ml) and a drop of TFA and purified by HPLC C18. The appropriate fractions were collected and concentrated in vacuo to afford the subtitle compound (100 mg, 60%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]([C:14]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[C:7]([Br:6])[CH:15]=1)=[O:17]
Reactant: NCCCO
Reactant: O=C(O)c1cc(Br)c2cc[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCO)c1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
3-Aminopropanol (1.36 g, 18.1 mmol) was added to a solution of 4-bromo-1H-indole-6-carboxylic acid (4.35 g, 18.1 mmol), triethylamine (4.60 mL, 45.3 mmol), and O-benzotriazol-1-yl-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (6.87 g, 18.1 mmol) in DMF (40 mL) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (10% methanol in dichloromethane) to yield 3.0 g (56%) of 4-bromo-1H-indole-6-carboxylic acid (3-hydroxy-propyl)-amide. Mass spectrum (LCMS, ESI pos.): Calcd for C12H13BrN2O2 296.02. Found 296.9; (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:28]1([C:31]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 28.9 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) in N,N-dimethylacetamide (5 mL) was added cyclopropanecarbonyl chloride (76.0 μL, 0.836 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (103 mg, 29%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.C([C:18]1[C:19]([N:27]=[CH:28][N:29]([CH3:31])C)=[N:20][C:21]([CH:24]2[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:24]1([C:21]2[CH:22]=[CH:23][C:18]3[C:31]([NH:8][C:6]4[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=4[S:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:29][CH:28]=[N:27][C:19]=3[N:20]=2)[CH2:25][CH2:26]1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Sc2ccccc2)c(Nc2ncnc3nc(C4CC4)ccc23)c1

Procedure:
The product from Example 7f was reacted with the product from Example 77A using the procedure from Example 73 substituting the product from Example 7f for the product from Example 9c and substituting the product from Example 77A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.05-1.19 (m, 4 H), 2.22-2.41 (m, 1 H), 2.35 (s, 3 H), 7.05-7.31 (m, 7 H), 7.37 (s, 1 H), 7.58 (d, J=8.46 Hz, 1 H), 8.50 (s, 1 H), 8.65 (d, J=8.46 Hz, 1 H), 10.21 (s, 1 H); MS (ESI)+ m/z 385 (M+H)+.