Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:44]=[CH:43][C:12]([CH2:13][N:14]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>CO>[NH2:35][CH2:34][CH2:33][N:14]([CH2:13][C:12]1[CH:43]=[CH:44][C:9]([Cl:8])=[CH:10][CH:11]=1)[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1)=[O:16]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)N(CCN)Cc4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of HCl/dioxane at 0° C. was added to (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamido)ethylcarbamate (40 mg, 0.075 mmol) in MeOH (1 mL). The reaction mixture was stirred at 25° C. for 1 hour. After removal of the solvent, the crude product was purified by preparative HPLC to afford (R)—N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide (32 mg, 90%). MS (ESI) m/e (M+H+) 429.2. 1H NMR: δ=8.56 (s, 1H), δ=7.23-7.56 (dd, 4H), δ=4.51 (s, 2H), δ=3.97-4.19 (m, 4H), δ=3.70 (m, 1H), δ=3.61 (m, 4H), δ=3.40-3.43 (t, 2H), δ=2.96-3.15 (m, 4H), δ=2.42 (m, 1H), δ=1.89 (m, 1H), δ=1.21-1.22 (d, 3H).
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[O:18]=[C:4]([NH:26][CH2:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=O)COc1ccc(C(=O)OCC)cc1
Reactant: NCc1cccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1ccc(OCC(=O)NCc2cccnc2)cc1
Reaction time: 24 h
Yield: 95.4 %

Procedure:
2.9 g (11 mmole) of ethyl 4-(2-ethoxy-2-oxoethoxy)benzoate, 1.4 g (12 mmole) of 3-picolylamine and 2.1 g (1.3 mmole) of DBU were dissolved in ethanol (12 ml), and reaction was then carried out for 24 hours. After the reaction mixture had been concentrated, partition was carried out between ethyl acetate and water. The organic layer was then treated in an ordinary manner to obtain 3.3 g (yield: 90%) of ethyl 4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}benzoate.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([Br:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[OH:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[Br:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:14][C:9]2[C:8]3[O:24][C:26](=[O:28])[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]=3[CH:12]=[C:11]([CH3:13])[N:10]=2)=[C:16]([CH3:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)n1c(=O)oc2c(Oc3c(C)cc(Br)cc3C)nc(C)cc21
Reaction time: 8 h
Yield: 177.2 %

Procedure:
To a 0° C. solution of 4-(1-ethyl-propylamino)-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-pyridin-3-ol (40 mg, 0.101 mmol) was added triphosgene (10 mg, 0.035 mmol) and triethylamine (7 mg, 0.07 mmol) in 1 ml of dry THF. The resulting mixture was stirred overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified through silica gel column chromatography to give 26 mg (61%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.22(s,2H), 6.60(s,1H), 4.02(m,1H), 2.31(s,3H), 2.12(s,6H), 1.8–2.2(m,4H), 0.94(t,6H)ppm.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH:24]([N:27]([CH:30]([CH3:32])C)CC)([CH3:26])C.CS(OS(C)(=O)=O)(=O)=O.S([O-])(=O)(=O)C.N1CCCC1>C(Cl)Cl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:27]5[CH2:24][CH2:26][CH2:32][CH2:30]5)[CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CO)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: C1CCNC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CN2CCCC2)c1
Reaction time: 2.5 h

Procedure:
To {3-[(1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]phenyl}methanol (15 mg, 0.049 mmol, from Example 36, Step 1) in DCM (1.0 mL) was added diisopropylethylamine (26 μL, 0.15 mmol) followed by methanesulphonic anhydride (17 mg, 0.098 mmol). After mesylate formation was determined to be complete as judged by LCMS, solvent was removed in vacuo and the residue was re-dissolved in a mixture of THF (0.50 mL) and methanol (0.50 mL). Pyrrolidine (0.016 mL, 0.20 mmol, Aldrich) was added and the reaction was stirred for 2.5 hours. The product was purified using preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (11.4 mg, 65%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[S:50][C:51]([CH3:54])=[CH:52][N:53]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[S:50][C:51]([CH3:54])=[CH:52][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Reactant: Cc1cnc(N)s1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
A solution of triphenylphosphine (345 mg, 1.31 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (234 mg, 1.31 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (prepared as in Example 128, 300 mg, 1.01 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-amino-5-methylthiazole (288 mg, 2.52 mmol). The resulting reaction mixture was allowed to stir at 25° C. for 20 h. The reaction mixture was then diluted with water (30 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (30 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methyl-thiazol-2-yl)-propionamide (223 mg, 56%) as a pale yellow foam: mp 81–85° C. (foam to gel); [α]23589=−40.4° (c=1.01, chloroform); EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1225.
Reaction SMILES: O=[C:2]1[CH2:10][CH:9]2[CH2:11][C:5]3([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]([CH2:12][CH:3]1[CH2:4]3)[CH2:8]2.[NH2:21][OH:22].Cl.[OH-].[Na+]>CCO.O>[OH:22][N:21]=[C:2]1[CH2:10][CH:9]2[CH2:11][C:5]3([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]([CH2:12][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(=O)C(CC(C3)C1)C2
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC12CC3CC(=NO)C(CC(C3)C1)C2
Temperature: 80 °C
Yield: 90 %

Procedure:
The mixture of ketone 1D (10 mmol), NH2OH—HCl (5 mmol), and NaOH (5 mmol) was diluted with EtOH (5 mL) and H2O (1 mL) and the reaction mixture was heated at 80° C. for 16 h. Upon cooling, the reaction mixture was extracted with DCM (10 mL×3) and the combined organic layers were dried (Na2SO4) and concentrated to provide oxime 12A in 90% yield as a solid. The material was used in the next step without further purification. Data: LC/MS (ESR) m/z 295 [M+1]+.
Reaction SMILES: ClC1C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.[OH-].[K+:17]>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S-:15])=[CH:11][CH:10]=1.[K+:17]
Reactant: Sc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: [S-]c1ccc(Cl)cc1

Procedure:
A 4-necked, 1-liter flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser tube was charged with a monochlorobenzene solution (0.871 mole of 4-chlorothiophenol) of 4-chlorothiophenol (13.3% of impurities) prepared by the process of Example 2 and 520 g (0.929 mole) of an aqueous solution of 10 wt % potassium hydroxide. The mixture was reacted at 25° C. for 15 minutes and was subjected to separation procedure to give an aqueous solution of potassium 4-chlorothiophenolate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:6]1[C:5]2[NH:1][N:2]=[N:3][C:4]=2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c2[nH]nnc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
1H-Benzotriazole-5-carboxylic acid (1 g, 6 mmol) was dissolved, in conc. sulphuric acid (20 ml) and cooled to 0° C. on an ice bath. Nitric acid (20 ml, excess) was added drop wise to the cooled solution over a period of 20 minutes. Stirring was continued for another 15 minutes at 0° C. and then at 90° C. for 2 hours, by which time TLC (A) indicated the conversion of starting material. The solution was cooled to room temperature and poured over ice to precipitate a white solid. The solid was collected by filtration and washed with copious amounts of water until neutral to afford [21] in 48% yield. Rf (A) 0.53; δH(400 MHz; DMSO-d6) 8.77 (1H, s, BT) 9.01 (1H, s, BT) 13.75 (1H, br s, OH) 16.90 (1H, s, NH); m/z (EI−HR) 208.02288 [(M) calc. for C7H4N4O4 208.02325].
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([N:1]4[CH2:2][CH:3]([N:5]5[CH2:6][CH2:7][N:8]([C:11]([C:13]6[S:14][CH:15]=[CH:16][N:17]=6)=[O:12])[CH2:9][CH2:10]5)[CH2:4]4)=[O:35])=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reactant: O=C(O)c1ccc2c(c1)CCN2c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc2c(c1)CCN2c1ccc(F)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 55d (30.9 mg, 0.12 mmol), and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with H2O, aqueous NaHCO3 and brine, and then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give compound Cpd 885 (44.4 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.38 (dd, J=8.3, 1.7 Hz, 1H), 7.16-7.25 (m, 2H), 7.03-7.12 (m, 2H), 6.88 (d, J=8.3 Hz, 1H), 4.05-4.67 (m, 6H), 3.99 (t, J=8.6 Hz, 2H), 3.76-3.94 (m, 2H), 3.20-3.30 (m, 1H), 3.16 (t, J=8.6 Hz, 2H), 2.37-2.64 (m, 4H); MS m/z (M+H+) 492.1.
Reaction SMILES: [NH3:1].CC(O)C.[F:6][C:7]([F:41])([CH2:13][C:14]1([OH:40])[C:27]2[CH:26]=[C:25]([O:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][C:17]([C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)=[CH:18][CH:19]=2)[C:8]([O:10]CC)=O>>[F:41][C:7]([F:6])([CH2:13][C:14]1([OH:40])[C:27]2[CH:26]=[C:25]([O:28][CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][C:17]([C:34]1[CH:39]=[N:38][CH:37]=[N:36][CH:35]=1)=[CH:18][CH:19]=2)[C:8]([NH2:1])=[O:10]
Reactant: CCOC(=O)C(F)(F)CC1(O)c2cc(OCC(C)(C)C)ccc2Oc2ccc(-c3cncnc3)cc21
Reactant: N
Solvent: CC(C)O
Product: CC(C)(C)COc1ccc2c(c1)C(O)(CC(F)(F)C(N)=O)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ammonia, as a 2 M solution in iPrOH (15 mL, 30.0 mmol), was added to ethyl 2,2-difluoro-3-(9-hydroxy-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-yl)propanoate (0.100 g, 0.201 mmol) at room temperature. After 30 minutes of stirring at RT the solution was concentrated to afford 2,2-difluoro-3-(9-hydroxy-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-yl)propanamide. M=470.3 [M+H].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.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>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Oc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A mixture under N2 in DMF (18 mL) of 4-iodophenol (2.00 g, 9.09 mmol), 4-fluorophenylboronic acid (1.40 g, 10.0 mmol), cesium carbonate (4.44 g, 13.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.23 mmol) was stirred for 10 minutes at ambient temperature and then overnight at reflux. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and extracted twice with water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (10:1, then 5:1 hexanes-ethyl acetate) gave 4-(4-fluorophenyl)phenol (0.79 g, 46%) as a white powder.
Reaction SMILES: [OH:1][C:2]1([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:21]=2[O:29][CH3:30])[C:10](=[O:11])[C:9]2[C:4](=[C:5]([N+:16]([O-])=O)[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].Cl.O>C(O)C.[Fe]>[NH2:16][C:5]1[CH:6]=[CH:7][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[C:9]2[C:4]=1[C:3](=[O:19])[C:2]([OH:1])([C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][C:21]=1[O:29][CH3:30])[C:10]2=[O:11]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2c(NC(C)=O)ccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2c(N)ccc(NC(C)=O)c2C1=O
Yield: 70.8 %

Procedure:
N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3 ml). This solution was added with iron (0.098 g), conc. HCl (0.05 ml) and water (0.3 ml). The reaction mixture was heated for 2 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (65 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][N:15]([C:25]3[N:26]=[N:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=3)[C:12]2=[CH:13][N:14]=1.[BH4-].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([CH:18]([OH:24])[CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:16][N:15]([C:25]3[N:26]=[N:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=3)[C:12]2=[CH:13][N:14]=1
Reactant: CCC(CC)C(=O)c1cn(-c2ccc(OC(C)C)nn2)c2cnc(-c3c(C)cccc3C)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(CC)C(O)c1cn(-c2ccc(OC(C)C)nn2)c2cnc(-c3c(C)cccc3C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[5-(2,6-dimethyl-phenyl)-1-(6-isopropoxy-pyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one (70 mg, 0.15 mmol) in a (4:1) EtOH—H2O mixture (5 mL) −30° C., NaBH4 (50 mg, 1.3 mmol) is added, and the mixture is allowed to gradually warm up to room temperature at which the stirring is continued for 2 h. The mixture is concentrated under reduced pressure. The residue is diluted with a saturated aqueous solution of Rochelle's salt (10 mL), and the product is extracted with DCM. The combined organic solutions are washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Chromatography of the residue on silica gel (hexane-EtOAc, 1:1) gives 1-[5-(2,6-dimethyl-phenyl)-1-(6-isopropoxy-pyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-ol as colorless oil. 1H NMR (CDCl3) 9.52 (s, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.22-7.10 (m, 3H), 5.62 (m, 1H), 5.21 (m, 1H), 2.08 (s, 6H), 1.47 (d, J=7 Hz, 6H), 1.08 (s, 9H); LCMS m/z 459.14 (2.48 min).
Reaction SMILES: [NH+]1NN=NC=1.C(C1C=CC(S([O-])(=O)=O)=CC=1)CCCCCCCCCCC.[Na+].[N+:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[CH:35]2)([O-])=[O:30]>>[N:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[CH:35]2)=[O:30]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: CCCCCCCCCCCCc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: c1nn[nH][nH+]1
Product: O=Nc1ccc2[nH]ncc2c1

Procedure:
Next, a protective layer to which were added 700 ml/mol Ag of tetrazolium compound T-6 represented by Formula T, 300 mg of sodium p-dodecylbenzenesulfonate and 80 mg/mol Ag of 5-nitroindazole was coated according to double-jet process, and this was designated as Sample (1). Also, a protective layer, to which 5-nitrosoindazole and 2.5 g per mol of Ag of cyclodextrin Isoelite P, produced by Ensuikoseito Co., were added, was coated also according to double-jet process. This was designated as Sample (2).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCOCC.[H-].C([Al+]CC(C)C)C(C)C>O>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(C)(C)c1ccc(C2=CC(O)CCC2)c(O)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a -30° C. solution of 1.00 g. (3.18 mmole) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-cyclohexenone in 60 ml. of ether was added dropwise 6.3 ml. of a 1 M (in toluene) diisobutylaluminum hydride solution. The reaction was stirred 30 min. longer at -30° C. and then added to 1.5 1. water. The quenched solution was extracted with three 400 ml. portions of ether and the combined extracts washed twice with 125 ml. of saturated sodium chloride and dried over magnesium sulfate. After evaporation the crude product was purified via column chromatography on 50 g. of florial eluted with ether to yield an oil. Crystallization of the oil from pentane gave 256 mg. (25%) of the title product.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2s1
Yield: 42 %

Procedure:
Prepared from VII and 3,4-dichloroaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 42%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2851, 2225, 1644, 1612, 1579, 1456, 1378, 1355, 1308, 1270, 1241, 1168, 1122, 1026, 971, 879, 834, 816; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=8.7 Hz), 8.30 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.63-7.53 (m, 2H), 7.30 (m, 2H); HRMS calcd for C16H8N5SCl2 (M+H+): 371.9877, found 371.9882.
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CC[CH:34]([CH:37]2[CH2:42][CH2:41][CH:40]([C:43]([OH:45])=[O:44])[CH2:39][CH2:38]2)CC1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:34]([CH:37]4[CH2:42][CH2:41][CH:40]([C:43]([OH:45])=[O:44])[CH2:39][CH2:38]4)[CH2:13][CH2:12]3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: O=C(O)C1CCC(C2CCNCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: O=C(O)C1CCC(C2CCN(Cc3ccc([C@H]4COc5cccnc5O4)cc3)CC2)CC1

Procedure:
Compound 265 is prepared from Intermediate C and 4-piperidin-4-yl-cyclohexanecarboxylic acid according to General Method H. (LC/MS method 16: ES+ m/z 437.4 [M+H]+, Rt=2.58 min).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])[CH3:20])C1C=CC=CC=1.O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])[CH3:20]
Reactant: C[C@H](Cc1c[nH]c2c(OCc3ccccc3)cccc12)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(O)cccc12)N1C(=O)c2ccccc2C1=O
Temperature: 95 °C
Reaction time: 1 h

Procedure:
(R)-7-Benzyloxy-3-(2-phthalimidopropyl)indole 12.16 g was dissolved in 400 ml of ethanol, and a water 100 ml suspension of a 10% palladium on carbon catalyst (content 50%) 4.00 g prepared separately was added thereto. Ammonium formate 6.00 g was added thereto while stirring, and the suspension was heated in an oil bath of 95° C. For one hour. After cooling down, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Acetone was added to the residue, and a deposited salt was filtered off. The filtrate was concentrated under reduced pressure, whereby 10.27 g of a residue containing the title compound was obtained.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[N:16]=[CH:15][C:14]=3[N:27]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH:31]1([CH2:30][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:11]3[O:12][C:13]4[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[N:16]=[CH:15][C:14]=4[N:27]=3)=[CH:5][C:4]=2[O:3][CH:2]([F:1])[F:28])[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(OC(F)F)c3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)c(OC(F)F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(3-(difluoromethoxy)-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.