Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14]O[C:11]=3[C:10]=2[C:18]([OH:20])=O)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(Cl)(Cl)=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:9]3[CH:17]=[CH:16][C:12]4[O:13][CH2:14][O:26][C:11]=4[C:10]=3[C:18]2=[O:20])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2ccc3c(c2C(=O)O)OCO3)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)c1c-2ccc2c1OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
Crude 5-(4-methoxyphenyl)-1,3-benzodioxole-4-carboxylic acid was dissolved in thionyl chloride (10 mL) and refluxed for 6 h. The reaction was cooled to ambient temperature and the solvent was removed by rotary evaporation to give the crude acid chloride. The acid chloride was dissolved in methylene chloride (10 mL) and added to a suspension of aluminum chloride (0.67 g, 5.00 mmol) in methylene chloride (10 mL). The reaction was stirred at ambient temperature for 4 h and quenched with a mixture of ice and concentrated HCl. The mixture was extracted with methylene chloride and dried with magnesium sulfate and concentrated by rotary evaporation to afford 89 mg of 8-methoxy-10H-fluoreno[1,2-d]-1,3-dioxol-10-one (0.35 mmol, 45% yield). 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.06 (d, J=2.2, 1H), 6.88 (dd, J=8.3, 2.2 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.15 (s, 2H), 3.86 (s, 3H). Sodium hydride (21 mg, 0.53 mmol) was suspended in THF (5 mL) and diethyl cyanomethylphosphonate (94 mg, 0.53 mmol) was slowly added to the suspension. After 15 min a yellow solution resulted and a solution of 8-methoxy-10H-fluoreno[1,2-d]-1,3-dioxol-10-one (89 mg, 0.35 mmol) in THF (5 mL) was added dropwise. The solution was allowed to stir at ambient for 16 h. The solvent was removed by rotary evaporation and the residue was taken up in methylene chloride, washed with water, and dried with magnesium sulfate. The solvent was removed by rotary evaporation to yield the crude Horner-Emmons product as an orange solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][C:28]=1[F:34]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:29][C:28]=1[F:34]
Reactant: COC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.084 g, 0.28 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (U.S. Pat. No. 6,252,090, 0.091 g, 0.3 mmol), triethyl amine (3 mL), copper(I)iodide (0.027 g, 0.14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) followed by flash column chromatography over silica gel (230-400 mesh), the title compound was obtained as a yellow oil (0.083 g, 64%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.C1COCC1.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH2:10]([N:9]([CH2:8][C:7]1[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:13][CH2:14][CH3:15])[CH2:11][CH3:12]
Reactant: CCCN(CCC)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1ccc(N)cc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
The compound (492 mg) obtained in Example 19-1 was dissolved in methanol (5.0 ml) and THF (2.5 ml). Then, the solution was added with activated carbon (49.0 mg) and iron trichloride hexahydrate (manufactured by Kanto Kagaku) (4.90 mg), followed by refluxing under heating for 30 minutes. After the solution was cooled to room temperature, hydrazine monohydrate (0.35 ml) was added to the solution and then the whole was refluxed for 3 hours under heat. After completion of the reaction, the reaction product was filtrated through Celite and the solvent was then distilled off. After the addition of water, chloroform extraction was performed. The extract was dried with anhydrous magnesium sulfate. The solvent was distilled off, thereby obtaining the subject compound (437 mg) as a yellow oily substance.
Reaction SMILES: C([O:8][P:9]([O:19][CH2:20][C@@H:21]([N:26]1[C:35]2[C:30](=[CH:31][C:32](Br)=[CH:33][N:34]=2)[C:29](=[O:37])[C:28]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:27]1)[CH2:22][CH:23]([CH3:25])[CH3:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])C1C=CC=CC=1.[CH2:43]([NH:45][C:46](=[O:66])[NH:47][C:48]1[N:53]=[CH:52][C:51](B(O)O)=[C:50]([C:57]2[S:58][CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[N:61]=2)[CH:49]=1)[CH3:44].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([O:11][P:9]([O:19][CH2:20][C@@H:21]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([C:51]3[CH:52]=[N:53][C:48]([NH:47][C:46](=[O:66])[NH:45][CH2:43][CH3:44])=[CH:49][C:50]=3[C:57]3[S:58][CH:59]=[C:60]([C:62]([F:65])([F:63])[F:64])[N:61]=3)=[CH:33][N:34]=2)[C:29](=[O:37])[C:28]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:27]1)[CH2:22][CH:23]([CH3:25])[CH3:24])([OH:8])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cn([C@H](COP(=O)(OCc2ccccc2)OCc2ccccc2)CC(C)C)c2ncc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](COP(=O)(O)OCc2ccccc2)CC(C)C)cn1
Temperature: 80 °C
Yield: 39.2 %

Procedure:
In a round bottomed flask ethyl 1-[(2S)-1-{[bis(benzyloxy)phosphoryl]oxy}-4-methylpentan-2-yl]-6-bromo-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 28, 700 mg, 1.05 mmol), 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 565 mg, 1.28 mmol) and aqueous sodium carbonate (125 mg, 1.18 mmol) were combined and suspended in dimethylformamide (10 mL). Argon gas was purged through the above suspension for 15 min. Tetrakis (triphenylphosphine) palladium (122 mg, 0.10 mmol) was added under argon atmosphere and the reaction mixture was heated to 80° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, the filtrate was poured into water to give a solid. The solid was filtered and washed with water then dried to afford 330 mg (50%) of ethyl 1-[(2S)-1-{[(benzyloxy)(hydroxy)phosphoryl]oxy}-4-methylpentan-2-yl]-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [CH2:1]([N:6]1[C:11]([S:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:21]([CH3:23])[CH3:22])[C:9](=[O:24])[NH:8][C:7]1=[O:25])[CH:2]=[CH:3][CH2:4]C.C(N1C(SC2C=C(C)C=C(C)C=2)=C(C(C)C)C(=O)NC1=O)C=CC1C=CC=CC=1.COC(C=CCN1C(SC2C=C(C)C=C(C)C=2)=C(C(C)C)C(=O)NC1=O)=O.C(N1C(SC2C=C(C)C=C(C)C=2)=C(C(C)C)C(=O)NC1=O)C#CC.C1(C#CCN2C(SC3C=C(C)C=C(C)C=3)=C(C(C)C)C(=O)NC2=O)C=CC=CC=1>>[CH2:1]([N:6]1[C:11]([S:12][C:13]2[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:10]([CH:21]([CH3:22])[CH3:23])[C:9](=[O:24])[NH:8][C:7]1=[O:25])[CH:2]=[CH:3][CH3:4]
Reactant: CCC=CCn1c(Sc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: CC#CCn1c(Sc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: COC(=O)C=CCn1c(Sc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC#Cc2ccccc2)c1
Product: CC=CCn1c(Sc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O

Procedure:
1-(2-pentenyl)-5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-cinnamyl-5-isopropyl-6-(3, 5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(methoxycarbonylallyl)-5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(2-butynyl)-5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(3-phenyl-2-propynyl)-5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione;
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([OH:17])[N:11]=[CH:10]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([OH:17])[N:11]=[CH:10]2)=[CH:18][CH:19]=1
Reactant: NC(=O)c1c(O)ncn1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(O)ncn1Cc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
1 g (3.81 mmol) of 3-(4-nitrobenzyl)-5-hydroxy-3H-imidazole-4-carboxamide is placed in 30 ml of methanol with 100 mg of palladium-on-charcoal (51% water) in a hydrogenation flask. The medium is flushed with argon and then with hydrogen for 30 minutes with stirring. The medium is again flushed with argon and the catalyst is filtered off by suction. The solvent is evaporated off to give 0.710 g of a yellowish-white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:17]([CH2:20][CH:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[N:18][N:19]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[C:7]([CH3:16])[CH:6]=2.[O:27]1CCCC1.[OH-].[Na+].Cl>CO>[CH3:16][C:7]1[CH:6]=[C:5]2[C:10]([NH:11][C:2](=[O:27])[C:3]3[N:4]2[C:17]([CH2:20][CH:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[N:18][N:19]=3)=[CH:9][C:8]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc2nc(Cl)c3nnc(CC4CCSCC4)n3c2cc1C
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(=O)O)[nH]c(=O)c1nnc(CC3CCSCC3)n12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 1.70 g of methyl 4-chloro-8-methyl-1-(tetrahydro-2H-thiopyran-4-ylmethyl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate, 18.0 mL of tetrahydrofuran, and 18.0 mL of methanol was added 9.20 mL of a 3 M aqueous sodium hydroxide solution, followed by stirring at 60° C. overnight. 3 M hydrochloric acid was added thereto to adjust the pH to about 3, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1.20 g of 8-methyl-4-oxo-1-(tetrahydro-2H-thiopyran-4-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O.O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: [F-]
Reactant: Fc1ccc2c(OC3CC3)cnc(Cl)c2c1
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2c(OC3CC3)cnc(F)c2c1
Temperature: 145 °C
Yield: 67.1 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-cyclopropoxyisoquinolin (0.24 g, 1.01 mmol) in DMSO (2 ml) was added cesium fluoride (0.38 g 2.52 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.15 g 67%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)(=[O:26])=[O:25])[CH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][C:18]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:35][CH:34]=4)[CH:30]=[CH:31]3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CCS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl-4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxy late (intermediate-6) and 5-(ethylsulfonyl)-1H-indole (intermediate-81).
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].[CH3:6][O:7][C:8](=[O:28])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[C:11]([O:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[C:22]([F:27])[CH:21]=2)[CH:10]=1.O.[Cl-].[Na+].O.N.C(OC(=O)C)C>CS(C)=O.[Cu](I)I>[CH3:6][O:7][C:8](=[O:28])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[C:11]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:22]([F:27])[CH:21]=2)[CH:10]=1
Reactant: CS(=O)[O-]
Reactant: COCOc1cc(Oc2ccc(Br)c(F)c2)cc(C(=O)OC)c1
Agent: I[Cu]I
Agent: N
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)cc(C(=O)OC)c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 47.6 %

Procedure:
After adding 757 mg (7.41 mmol) of sodium methanesulfinate and 1.41 g (7.41 mmol) of copper iodide to a solution of 357 mg (0.93 mmol) of the obtained ester compound in dimethylsulfoxide (6.0 ml), the reaction mixture was stirred at 120° C. for 6 hours. Sodium chloride water-ammonia water (9:1) was added to the reaction mixture and extraction was performed with acetic acid ethyl ester, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=2:1) to obtain 170 mg of 3-(3-fluoro-4-methanesulfonyl-phenoxy)-5-methoxymethoxybenzoic acid methyl ester (yield: 48%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1OC)([O-:3])=O.[NH2:12][NH2:13]>>[OH:3][N:1]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:13]=[N:12]1
Reactant: NN
Reactant: COc1ccncc1[N+](=O)[O-]
Product: On1nnc2ccncc21

Procedure:
3-nitro-4-methoxy pyridine is reacted with hydrazine in accordance with the procedure of Example 1 to yield the above-identified compound.
Reaction SMILES: [CH:1]1([O:7][CH:8](C)[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(N(CC)CC)C.ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(CO)OC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Yield: 78.7 %

Procedure:
To a solution of 2-cyclohexyloxy-1-propanol (4.0 g, 28 mmol) in triethylamine (5.8 ml) and dichloromethane (250 ml) was added 4-bromobenzenesulfonyl chloride (7.87 g, 31 mmol) at 0° C. under nitrogen, and the resultant mixture was stirred for 16 h at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine (100 ml each), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by silica (200 g) column chromatography using a gradient elution of hexane:ethyl acetate (6:1 to 1:1) to give the title compound as a white crystalline solid (8.0 g, 80% yield).
Reaction SMILES: [I:1][C:2]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21]1(=O)[CH2:24][CH2:23][CH2:22]1.C1(N2CCC3C=C(I)C(OC4N=CC(C(NC)=O)=CC=4)=CC=3CC2)CCC1>>[CH:21]1([N:8]2[CH2:7][CH2:6][C:5]3[CH:11]=[C:12]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:2]([I:1])=[CH:3][C:4]=3[CH2:10][CH2:9]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCC1
Reactant: Ic1cc2c(cc1OCc1ccccc1)CCNCC2
Agent: CNC(=O)c1ccc(Oc2cc3c(cc2I)CCN(C2CCC2)CC3)nc1
Product: Ic1cc2c(cc1OCc1ccccc1)CCN(C1CCC1)CC2

Procedure:
Example 226 (E226) was prepared from 7-iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (D45) and cyclobutanone using the method described for Example 225 (E225); MS (ES+) m/e 434 [M+H]+.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][C:9]2[C:10]([NH:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[N:11][C:12]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:16]=3)=[N:13][CH:14]=2)[CH2:4][O:3]1.[ClH:40]>C(#N)C>[ClH:40].[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([C:12]2[N:11]=[C:10]([NH:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:9]([O:8][CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])=[CH:14][N:13]=2)=[N:16]1
Reactant: CC1(C)OC[C@H](COc2cnc(-c3nn(Cc4ccccc4F)c4ccccc34)nc2Nc2ccncc2)O1
Agent: Cl
Solvent: CC#N
Product: OC[C@@H](O)COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
124 mg of 5-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)pyrimidin-4-amine (0.24 mmol, 1. eq.) were dissolved in 12 ml of acetonitrile. 515 μl of conc. hydrogen chloride (6.00 mmol, 20.8 eq.) were added dropwise. The reaction mixture was stirred at room temperature for 18 hours. The suspension was filtered off and washed with acetonitrile. The precipitate was dried at 45° C. under vacuo to yield 119 mg (0.23 mmol, 97%) of the analytically pure target compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:16]1([CH2:21][C@@H:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)O)[CH:20]=[CH:19][N:18]=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:16]1([CH2:21][C@H:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[O:1][C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C1CCCc2c1ccc(O)c2[N+](=O)[O-]
Reactant: O[C@@H](Cn1ccnc1)c1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1cccnc1)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of 6-hydroxy-5-nitro-1-tetralone (0.957 g, 4.62 mmol) in dry THF (20 mL) was added (R)-2-imidazol-1-yl-1-pyridin-3-yl-ethanol (0.875 g, 4.62 mmol) followed by triphenylphospine (1.33 g, 5.08 mmol). After approximately 10 min, diethylazodicarboxylate (0.80 mL, 5.08 mmol) was added slowly. The reaction became homogenous. The reaction was allowed to stir at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was triturated with Et2O to remove some of the phospine by-products. The residue was dissolved in EtOAc and washed with H2O, saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated to give a foam/oil. Purification by chromatography (SiO2, 4-10% MeOH/CH2Cl2) afforded the title compound as a tan foam (1.66 g, 4.39 mmol, 95%). The structure was confirmed by NMR and mass spectrometry. MS m/z 379 (M++H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:18]3[C:10](=[CH:11][N:12]=[C:13]4[C:17]=3[CH:16]=[CH:15][NH:14]4)[N:9]=[N:8]2)[CH2:2]1.[C:19]([CH2:21][C:22](O)=[O:23])#[N:20].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:23]=[C:22]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:18]3[C:10](=[CH:11][N:12]=[C:13]4[C:17]=3[CH:16]=[CH:15][NH:14]4)[N:9]=[N:8]2)[CH2:2]1)[CH2:21][C:19]#[N:20]
Reactant: c1cc2c(ncc3nnn([C@@H]4CCCNC4)c32)[nH]1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nnc3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To a stirred solution of (R)-1-piperidin-3-yl-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene (72 mg, 297 μmol) in DCM (15 ml) at 0° C., cyanoacetic acid (30.0 mg, 357 μmol), N-hydroxybenzotriazole (56.0 mg, 416 μmol), 4-(dimethylamino)pyridine (58.0 mg, 475 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (91.0 mg, 475 μmol) were added. The mixture was then stirred at ambient temperature for 18 hours. The crude reaction mixture was purified by column chromatography on silica gel (gradient: 0 to 6% methanol in DCM) affording 82 mg (92%) of 3-oxo-3-[(R)-3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-piperidin-1-yl]propionitrile. LCMS (Method A, ESI): RT=2.73 min, m+H=310.1; 1H NMR (400 MHz, DMSO-d6) δ: 12.38 (s, 1H), 9.02 (s, 1H), 7.64-7.59 (m, 1H), 7.12 (m, 1H), 5.28-4.96 (m, 1H), 4.81-4.31 (m, 1H), 4.20-3.70 (m, 3H), 3.36-2.96 (m, 2H), 2.44-1.68 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](O)=[O:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:57][O:58][C:59](=[O:64])[C:60]([NH2:63])([CH3:62])[CH3:61]>CN(C=O)C>[CH3:57][O:58][C:59](=[O:64])[C:60]([CH3:62])([NH:63][C:22]([C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]=1[O:11][CH:2]([CH3:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:23])[CH3:61]
Reactant: CC(COc1ccccc1)Oc1c(C(=O)O)ccc2ccccc12
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OC(C)COc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 100 mg—(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid in 1.5 ml abs. DMF under inert atmosphere 45 mg 1-hydroxybenzotriazole, 83 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 70 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 36 mg of 2-aminoisobutyric acid methyl ester hydrochloride, followed by 70 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 114 mg of 2-methyl-2-{[1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH:22]=[N:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3ccncc23)CC1
Agent: O=[Pt]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CNCC3)CC1
Yield: 69.9 %

Procedure:
The compound of Step 2 (2.8 g, 8.93 mmol) is dissolved in isopropanol (120 mL), and platinum oxide (1 g) is added. The mixture is pressurized to 45 psi under hydrogen and allowed to react for about 12 hours. The mixture is filtered, concentrated and chromatographed to give about 1.98 g of 8-(4-t-butyloxycarbonyl-piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline (70%).