Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].C(O[CH:10](OCC)[N:11]([CH3:13])[CH3:12])C>>[CH3:10][N:11]([CH3:13])[CH:12]=[CH:4][C:3](=[O:5])[CH:2]([CH3:6])[CH3:1]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)C(C)C
Product: CC(C)C(=O)C=CN(C)C
Yield: 80 %

Procedure:
3-Methylbutan-2-one (2.5 g, 1 eq.) and dimethylformamide diethylacetal (7.46 mL, 1.5 eq.) were heated at 100° C. for 4 days to give compound 85 as yellow viscous oil in 80% yield, which was used directly without further purification in the next step.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C[O-].[K+].[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:30])[CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Cc1ccccc1C(F)(F)F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
After dissolving 2.57 g of 2-(trifluoromethyl)benzaldehyde in 15 ml of methanol, 2.75 g of p-toluenesulfonyl hydrazide was added, the mixture was stirred at room temperature for 2 hours, and then 1.09 g of potassium methoxide and a methanol solution (4 ml) of 1.50 g of 1-benzylpiperidine-4-carboxaldehyde was added, and the mixture was shielded from light and stirred overnight at 55° C. The reaction solution was concentrated under reduced pressure, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: toluene/ethyl acetate) to obtain the title compound (1.30 g, 49% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[C:24]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:23]=1.[C:37]1(=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](=[O:46])[NH:38]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[C:33]([C:24]1[CH:23]=[C:22]([C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2][N:38]2[C:39](=[O:46])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37]2=[O:47])[CH:27]=[CH:26][C:25]=1[N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCBr)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
In a 50 mL three-necked flask under a nitrogen atmosphere, equipped with a magnetic stirrer, 1.0 g (1.82 mmol) of ethyl 4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate, 294 mg (2 mmol) of isoindole-1,3-dione and 276 mg of potassium carbonate (2 mmol) are placed in 20 mL of dimethylformamide. The reaction medium is heated at 100° C. for 3 hours and is then poured into water beforehand and acidified slightly with a 1 mol/L solution of hydrochloric acid, and extracted twice with ethyl acetate. The organic phases obtained are combined and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to give a brownish oil. This oil is purified by chromatography on silica (eluent: 80/20 heptane/ethyl acetate) to give 950 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-[1,1′;3′,1″]terphenyl-4-carboxylate (yield=86%) in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[O:11][CH3:12])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COC(CN)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(OC)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)-2-methoxyethanamine (0.071 g, 0.38 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.060 g, 0.16 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.022 g, 0.16 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.037 g, 0.19 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was loaded onto a Biotage SP1 system, eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 67 mg of the title compound (77% yield).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(OCc1ccccc1)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt are dissolved in 75 parts of hexamethylphosphoric triamide while heating to 110° C. After cooling to 20° C, 3.4 parts of (chloromethyl)benzene are added dropwise. Upon completion, stirring is continued for 18 hours at room temperature. The reaction mixture is poured onto 300 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding phenylmethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 76.7° C.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11](B1OC(C)(C)C(C)(C)O1)[CH2:12]2)=O)(C)(C)C.Br[C:26]1[C:30]2[CH:31]=[N:32][C:33]([NH2:47])=[C:34]([O:35][C@@H:36]([C:38]3[C:43]([Cl:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=3[Cl:46])[CH3:37])[C:29]=2[O:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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.COCCOC.O>[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][C:11]([C:26]1[C:30]3[CH:31]=[N:32][C:33]([NH2:47])=[C:34]([O:35][C@@H:36]([C:38]4[C:43]([Cl:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=4[Cl:46])[CH3:37])[C:29]=3[O:28][CH:27]=1)=[CH:10]2
Reactant: CC(C)(C)OC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1CC2
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CC4CCC(C3)N4)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a microwave vessel were added 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (60 mg, 0.2 mmol), 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-6-ylamine (0.098 g, 0.23 mmol), potassium carbonate (0.074 g, 0.54 mmol), DME/Water (4:1) (5 mL), and the vessel was degassed 3×. Pd(PPh3)4 (0.01 g, 0.009 mmol) was then added and the reaction mixture was heated in a microwave reactor to 100° C. for 30 min. The crude reaction mixture was passed through SPE cartridge. The compound was then dissolved in dioxane and 4 M HCl in 1,4-Dioxane (0.4 mL) was added slowly at 0° C. The reaction mixture was warmed to rt and stirred overnight at rt. Purification by prep TLC using 9% NH3 in MeOH in DCM afforded the title compound. 1H NMR (400 MHz, CD3OD): δ=1.64-1.77 (m, 1H), 1.85 (d, 3H), 1.89-1.98 (m, 1H), 2.01-2.12 (m, 2H), 2.18 (d, J=16.9 Hz, 1H), 2.88 (dd, J=16.8, 4.2 Hz, 1H), 3.82 (ddd, J=17.1, 5.8, 5.7 Hz, 2H), 6.46 (q, 1H), 6.52 (d, J=5.6 Hz, 1H), 7.19 (t, J=8.6 Hz, 1H), 7.37 (dd, J=9.0, 4.9 Hz, 1H), 7.54 (s, 1H), 8.16 (s, 1H). MS (ES+): m/z 447.97/450.01 (30/21) [MH+]. HPLC: tR=2.14 min (ZQ3, polar—5 min).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:5][CH:4]=1.[BrH:15]>>[BrH:15].[CH3:14][C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COc1ccc(-n2ccnc2C)cc1
Agent: Br
Product: Cc1nccn1-c1ccc(O)cc1
Yield: 69 %

Procedure:
A mixture of 4 parts of 1-(4-methoxyphenyl)-2-methyl-1H-imidazole and 37.5 parts of hydrobromic acid solution 48% is stirred and refluxed overnight. After cooling, the reaction mixture is evaporated. The residue is triturated in a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 3.8 parts (69%) of 4-(2-methyl-1H-imidazol-1yl)phenol monohydrobromide; mp. 181-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13])[CH:3]=1
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1cccc(Cl)c1
Product: C[C@@H](CCl)COc1cccc(Cl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:35]=[CH:34][C:10]([CH2:11][CH:12]([NH:24][S:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:13]3[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[N:3]1.N1C=C[CH:39]=[CH:38][C:37]=1S(C(NCC1C=CC(C2SC=CN=2)=CC=1)C1N=C(NCC(O)=O)C=CC=1)(=O)=O>C(O)(C)C>[CH:38]([O:22][C:21](=[O:23])[CH2:20][NH:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[CH:5][CH:4]=[N:3]3)=[CH:35][CH:34]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:18]=1)([CH3:39])[CH3:37]
Reactant: O=C(O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Reactant: O=C(O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OC(=O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 90 %

Procedure:
Reaction was carried out in the same manner as in Example 29 except for using (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid hydrochloride (25.8 mg, 0.0439 mmol) obtained in Example 7-(b) in place of (6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-ylamino)acetic acid, and using isopropanol (0.20 ml) in place of 1-hexanol. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (20.6 mg) as a colorless oil. (Yield: 90%)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][N:14]3C(C)C)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.OC1(C2C=C3C(C=CN3C(C)C)=CC=2)CCN(C)CC1>C(O)(C(F)(F)F)=O.C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1
Reactant: CC(C)n1ccc2ccc(C3=CCN(C)CC3)cc21
Agent: CC(C)n1ccc2ccc(C3(O)CCN(C)CC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1CC=C(c2ccc3cc[nH]c3c2)CC1

Procedure:
6-[N-Methyl-1,2,5,6-tetrahydropyridin-4-yl]-1-isopropyl-indole : from 6-[4-Hydroxy-1-methyl-piperidin-4-yl]-1-isopropyl-indole (20 mg, 0.0735 mmol) in 0.1 ml of TFA and 1 ml of THF at 60-64° C. Yield 4.8 mg (26%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([NH:15]C(=O)C)=[C:13]([F:19])[C:12]([F:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[CH2:1]([O:8][C:9]1[C:14]([NH2:15])=[C:13]([F:19])[C:12]([F:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1c(OCc2ccccc2)ccc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(OCc2ccccc2)ccc(F)c1F
Temperature: 90 °C

Procedure:
A round bottom flask containing N-(6-benzyloxy-2,3-difluorophenyl)-acetamide (1.0 g), potassium hydroxide (1.0 g), water (2 mL) and ethanol (10 mL) are heated at 90° C. for 10 h. The mixture is then concentrated and extracted twice with EtOAc and water. The combined organic layers are dried over MgSO4, filtered and concentrated. The product is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[F:11].[OH-].[Na+].Br[CH2:15][CH2:16]Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:11]
Reactant: ClCCBr
Reactant: N#CCc1ccc(Br)c(F)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc(Br)c(F)c2)CC1
Temperature: 60 °C

Procedure:
To a room temperature solution of (4-bromo-3-fluorophenyl)acetonitrile from Step 3 (6.4 g) in a solution of 7.5 mL of sodium hydroxide (50% in water W/W) were added 1-bromo-2-chloroethane (4.0 mL) and benzyltriethylammonium chloride (204 mg). The mixture was heated at 60° C. for 5 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). Extracted with ethyl acetate (200 mL). The extracts were washed with water (100 mL), hydrogen chloride (100 mL, 10% HCl in water) and brine. Then dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by swish using methyl t-butyl ether and hexanes to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][N:14]3[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:18]=4[C:17]4=[N:24][NH:25][C:26](=[O:27])[C:16]4=[N:15]3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.I[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[C:48]=1[CH3:54].C(=O)(O)[O-].[Na+]>CN(C)C=O.[Cu]I>[CH3:54][C:48]1[C:49]([CH3:53])=[CH:50][CH:51]=[CH:52][C:47]=1[N:25]1[C:26](=[O:27])[C:16]2=[N:15][N:14]([CH2:13][C:10]3[CH:11]=[N:12][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:8][CH:9]=3)[C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]2=[N:24]1
Reactant: Cc1cccc(I)c1C
Reactant: Cn1cc(-c2ccc(Cn3nc4c(=O)[nH]nc-4c4cccnc43)cn2)cn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1cccc(-n2nc3c4cccnc4n(Cc4ccc(-c5cnn(C)c5)nc4)nc-3c2=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-{[6-(1-Methyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one (50 mg, 0.14 mmol), copper(I) iodide (27 mg, 0.14 mmol, 1 equiv), potassium phosphate (0.18 g, 0.84 mmol, 6 equiv), (±)-trans-N,N′-bismethyl-1,2-cyclohexanediamine (59 mg, 0.42 mmol, 3 equiv) and 3-iodo-ortho-xylene (59 μL, 0.42 mmol, 3 equiv) were combined in degassed N,N-dimethylformamide (2.5 mL) and placed into an oil bath preheated to 110° C. for 30 minutes. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (25 mL, aqueous saturated) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.83 (1H, d, J=2.2 Hz), 8.78 (1H, dd, J=4.6, 1.7 Hz), 8.54 (1H, dd, J=8.0, 1.9 Hz), 7.92 (1H, dd, J=7.9, 2.2 Hz), 7.91 (1H, s), 7.89 (1H, s), 7.51 (1H, dd, J=8.0, 4.6 Hz), 7.41 (1H, d, J=8.3 Hz), 7.26 (1H, br s), 7.23-7.21 (2H, m), 5.96 (2H, s), 3.94 (3H, s), 2.36 (3H, s), 2.16 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 463.1986 [(M+H)+; calculated for C26H23N8O: 463.1989].
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:31])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[O:21][CH3:22])=[CH:8][C:7]([CH2:23][CH2:24][NH:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:6][CH:5]=2.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[Cl:1][C:2]1[N:3]([CH3:31])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:42][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[Cl:32])(=[O:41])=[O:40])=[O:18])=[CH:14][C:13]=1[O:21][CH3:22])=[CH:8][C:7]([CH2:23][CH2:24][NH:25][C:26]([N:28]([CH3:29])[CH3:30])=[O:27])=[CH:6][CH:5]=2
Reactant: COc1cc(C(=O)O)ccc1Cc1c(Cl)n(C)c2ccc(CCNC(=O)N(C)C)cc12
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cc1c(Cl)n(C)c2ccc(CCNC(=O)N(C)C)cc12

Procedure:
Using a similar procedure to that described in Example 2, part c, except starting from 4-[2-chloro-5-[2-(N',N'-dimethylureido)ethyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoic acid, and using 2-chlorophenylsulfonamide instead of 2-methylphenylsulfonamide, the title compound was obtained (94%) as a white solid: mp 204°-206° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCO.[H][H]>CN(C=O)C.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl(1-(4-nitrophenyl)piperidin-4-yl)carbamate (I74) (1.038 g, 3.230 mmol) was dissolved in dry DMF (15 mL), EtOAc (15 mL) and absolute EtOH (15 mL) under an atmosphere of nitrogen. 10% Pd/C (0.200 g) in EtOAc (5 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with balloon and stirred at room temperature for 18 hours. The catalyst was removed by filtration through celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a pink solid which was purified by silica gel chromatography using a gradient of 0-80% ethyl acetate in petroleum benzine 40-60° C. to give the title compound (I75) (0.730 g, 78%) as a purple-brown solid; 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J=8.6 Hz, 2H), 6.64 (d, J=8.7 Hz, 2H), 4.55-4.41 (m, 1H), 3.64-3.32 (m, 5H), 2.72 (t, J=11.0 Hz, 2H), 2.08-1.98 (m, 2H), 1.56 (ddd, J=23.7, 11.3, 3.9 Hz, 2H), 1.45 (s, 9H).). LCMS Method C: rt 0.38 min; m/z 292.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][O:20]C(=O)C2C=CC([N+]([O-])=O)=CC=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][OH:20])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NCCc1ccccc1COC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCCc1ccccc1CO)c1ccc([N+](=O)[O-])cc1
Yield: 92.3 %

Procedure:
1-(4-Nitrobenzoyl)amino-2-[2-(4-nitrobenzoyloxymethyl)phenyl]ethane (24 g) was added to a solution of 300 ml of methanol, 2.6 g of sodium hydroxide and 100 ml of water. The mixture was refluxed for 1 hour. After the reaction, the solvent was distilled off, and water was added. The crystals that precipitated were collected by filtration, washed with water, and recrystallized from ethanol-n-hexane to afford 14.8 g of 1-(4-nitrobenzoyl)amino-2-(2-hydroxymethylphenyl)ethane having a melting point of 137.3° to 137.6° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH:20]4[CH:15]([CH2:16][CH2:17][NH:18][CH2:19]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[CH3:37][O:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[C:40]=1[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:49][O:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:39]([O:38][CH3:37])[C:40]=1[C:41]([N:18]1[CH2:17][CH2:16][CH:15]2[CH:20]([N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:19]1)=[O:42]
Reactant: c1ccc(-c2ccnc(N3CC4CCNCC43)n2)cc1
Reactant: COc1cccc(OC)c1C(=O)O
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: COc1cccc(OC)c1C(=O)N1CCC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 8-(4-phenyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 6) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2,6-dimethoxy-benzoic acid for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C25H26N4O3, 430.50; m/z found, 431.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.60-7.27 (m, 7H), 7.25-6.66 (m, 3H), 4.84-2.46 (m, 12H), 2.18-1.15 (m, 4H).