Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>O1CCCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 10.0 g of 2-bromothiazole under nitrogen in 50 ml of tetrahydrofuran while cooling in a dry ice-acetone bath is added dropwise 36.6 ml of a 1.6M solution of butyl lithium via syringe. Stirring is continued for 1 hour. To the reaction mixture is added dropwise 29.8 g of tributyltin chloride in 20 ml of tetrahydrofuran. Stirred 1 additional hour. The reaction mixture is quenched with 20 ml of water and 50 ml additional water is added. After stirring for 20 minutes the reaction mixture is extracted with chloroform (3×60 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give 11.7 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24](O)[CH3:25]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([O:19][CH:24]([CH3:25])[CH3:23])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)C

Procedure:
The ester can be prepared by acid catalysed esterification of 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoic acid with/in 2-propanol. Isocratic HPLC method 2 (4.96 min.): 98.4%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])([O-])=O.[ClH:16]>CO.[Pd]>[ClH:16].[ClH:16].[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: CN(C)CCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CCNc1ccccc1N
Reaction time: 3.5 h

Procedure:
To a solution of N-(2-nitrophenyl)-N',N'-dimethylethylenediamine (9.70 g) in methanol (50 ml) were added concentrated hydrochloric acid (8 ml) and 10% palladium-on-carbon (0.97 g) and the mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 3.5 hours. The catalyst was filtered off and the filtrate was distilled off under reduced pressure to give 11.70 g of N-(2-aminophenyl)-N',N'-dimethylethylenediamine dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.[BH4-].[Na+]>CO.C(OCC)C>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(C=O)c(F)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COc1cc(CO)c(F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromine (15 mL, 0.3 mol) was added slowly to a solution of 2-fluoro-5-methoxy-benzaldehyde (23.1 g, 0.15 mol) in chloroform (500 mL) and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2-16% EtOAc in hexanes to give 4-bromo-2-fluoro-methoxy-benzaldehyde (20.7 g, 60%). To a solution of 4-bromo-2-fluoro-5-methoxy-benzaldeyde (4.0 g, 17.3 mmol) in MeOH at 0° C. was added NaBH4 (0.65 g, 17.3 mmol). After the reaction mixture was stirred at 0° C. for 2 hours, it was allowed to warm to room temperature. The organic layer was taked up in ethyl ether washed with water and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (25-45% EtOAc in hexanes) to give the product. (3.9 g, 99%). 1H NMR (300 MHz, CDCl3): δ 3.90 (s, 3H), 4.74 (d, J=6.02 Hz, 2H), 6.82 (q, J=6.1 Hz, 1H), 7.29 (d, J=10.58 Hz, 1H).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:16][N:17]([CH3:21])[C:18](=[O:19])[NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: CN(C)C(=O)Cl
Agent: Br
Product: CN(C)C(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrobromide is treated with dimethyl carbamoyl chloride using a procedure similar to that of Exmaple 5 to form 5-[4-(3,3-dimethylureido)phenyl]-2(1H)-pyrazinone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([S:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21

Procedure:
An appropriate indole is N-deprotonated and the resulting anion reacted with phenylsulfonyl chloride to provide the corresponding 1-phenylsulfonylindole. This protected indole may be purified or treated directly with an appropriate base, typically a lithium amide such as lithium diisopropylamide, and then reacted with an appropriate tropanone to provide the corresponding 3-hydroxy-3-(1-phenylsulfonylindol-2-yl)-8-azabicyclo[3.2.1]oct-2-ane.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccccc5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccccc5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1

Procedure:
A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (240 mg, 0.4 mmol, Step 3) in EtOAc (5 mL) was hydrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtOAc/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([O:6]C)=[O:5].N>CO.O>[CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Agent: N
Solvent: CO
Solvent: O
Product: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution (S)-methyl 3,3-dimethyl-2-(7-methyl-3-phenyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxamido)butanoate (Compound 86; 0.05 g, 0.13 mmol) in methanol/water was added 7N methanolic ammonia and the resulting mixture was stirred at 50° C. overnight. The mixture was concentrated, diluted with water and extracted with 10% i-PrOH/DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give Compound 281 (0.021 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ: 0.99 (s, 9H), 2.41 (s, 3H), 2.74 (m, 2H), 3.85 (s, 2H), 4.03 (t, 2H), 4.30 (d, 1H), 7.48 (m, 3H), 7.73 (m, 2H), 12.95 (s, 1H); LCMS (+ESI) m/z 371.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[Cl:2][CH2:3][CH:4]([NH:5][C:25](=[O:26])[C:24]1[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=1[F:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a slurry of 1.1 g of (+/-)-α-(chloromethyl)-4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-methanamine hydrochloride in 13 mL of ethyl acetate was added 0.60 g of 2.6-difluorobenzoyl chloride. 0.60 g of sodium bicarbonate, and 3 mL of water. After 15 min, ethyl acetate was added and the organic phase was washed with aqueous NaCl, dried (MgSO4), filtered, and concentrated to dryness. The residue was triturated with toluene/hexanes, filtered, washed with hexanes, and suction-dried to afford 1.22 g of product, m.p. 148-150° C. 1H-NMR (CDCl3): δ4.0 (dq, 2H), 5.6 (m, 1H), 6.75 (br d, 1H), 6.85 (t, 1H, J=60 Hz), 7.0 (t, 2H), 7.4 (m, 1H), 7.5 (d, 2H), 7.6 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH2:4][OH:5]
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
2-Amino-6-chlorobenzoic acid (25.0 g, 143 mmol) was dissolved in 120 mL of anhydrous THF in a 500 mL 2 neck round bottom flask. The solution was cooled in an ice-water bath. 215 mL of 1.0 M lithium aluminum hydride (LAH) THF solution was then added dropwise. After all of the LAH was added, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for overnight. ˜10 mL of water was added to the reaction mixture followed by 7 g 15% NaOH. An additional 20 g of water was added to the reaction mixture. Decant the organic THF phase and the solid was added with ethyl acetate. ˜200 mL and stirring and combined ethyl acetate organic portion and THF portion and added Na2SO4 drying agent. The mixture was filtered and evaporated. ˜20 g yellow solid was obtained without further purification for next step reaction.
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@@H:11]([OH:24])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(CC)CC.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@@H:11]([OH:24])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([O-:22])=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CCC1CN2CCC1CC2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([O-])c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 1.22 g dihydroquinidine (0.0037 mol) in 30 mL of CH2Cl2 was added 0.78 mL of Et3N (0.0056 mol; 1.5 eq), followed by 0.71 mL of p-chlorobenzoyl chloride (0.005 mol; 1.2 eq) in 1 mL CH2Cl2. After stirring 30 minutes at 0° C. and 1 hour at room temperature, the reaction was quenched by the addition of 10% Na2CO3 (20 mL). After separation, the aqueous layer was extracted with three 10 mL portions of CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent removed under vacuum. The crude product was purified as described above. Dihydroquinidine p-chlorobenzoate (1) was obtained in 91% yield (1.5 g) as a white foam.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6]C1C=C(C=CC=1)C(O[CH:13]1[C:18](=[O:19])[NH:17][C:16]([CH3:20])=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[S:14]1)=O.Cl>ClCCl.CO>[ClH:6].[CH2:1]([N:3]([CH2:4][CH3:5])[CH:13]1[C:18](=[O:19])[NH:17][C:16]([CH3:20])=[C:15]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[S:14]1)[CH3:2]
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reactant: CCNCC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)C1SC(c2ccncc2)=C(C)NC1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 78.4 %

Procedure:
Diethylamine (2.58 ml) was added to a solution of 2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.9 g) in dry dichloromethane (12 ml) and the mixture was stirred at ambient temperature for 21 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, was washed with saturated sodium bicarbonate aqueous solution and successively with water and was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (Wakogel C-200) column, using chloroform-methanol (=20:1) as an eluant to give pale yellow oily product. The oily product was dissolved in methanol and was adjusted to pH 2 by 2N hydrochloric acid. The solvent was removed under reduced pressure and the residue was washed with THF and allowed to stand to give the titled compound (0.685 g, yield 78.4%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[CH3:20][CH:21]([CH3:25])[CH2:22][CH2:23][NH2:24].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:24]3[CH2:23][CH2:22][CH:21]([CH3:25])[CH3:20])[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)CCN
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCC(C)C
Reaction time: 10 h
Yield: 56.3 %

Procedure:
4.6 g (0.01755 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.04 ml (0.01755 mol) of 3-methyl-butylamine were added thereto and the mixture was boiled for 24 hours on a water separator. After concentration the residue was hydro-genated with 1.8 g of Raney-nickel in 200 ml of ethanol at 120° and 140 bar for 10 hours. The material obtained was chromatographed over silica gel with cyclohexane/ethyl acetate 3:1. The product was dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 2.84 g (56%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-methyl-butyl)-2H-benzo[e]indol-2-one as white crystals with m.p. 81°-82° and 0.79 g (16%) of oily material from the mother liquors.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]=[C:57]=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:57]([NH:56][CH3:55])=[O:58])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: CN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and methyl isocyanate as the starting materials in 70% yield. LCMS for C25H28ClN8O3 (M+H)+: m/z=523.1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][OH:20])=[O:5].C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][O:20][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:41]([Cl:42])=[C:33]([Cl:32])[CH:34]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CO)s1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2COC(=O)c2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-3-hydroxymethyl-5-methyl[1,2,4]triazole (1.08 g) was dissolved in chloroform (50 ml). Triethylamine (0.34 g) and 3,4-dichlorobenzoyl chloride (0.69 g) were added, and the mixture was stirred at room temperature for 2 hours. Then, water was added to the solution for washing, and the mixture was dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent:ethyl acetate-methanol) and recrystallized from ethyl acetate-diisopropyl ether to give 1.10 g of (4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3,4-dichlorobenzoate.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](NC2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:4][C:3]=1S(O)(=O)=O.N1C(Cl)=NC(Cl)=NC=1Cl>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Clc1nc(Cl)nc(Cl)n1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-(3'-amino-2',4',6'-trimethyl-5'-sulfoanilino)anthraquinone-2-sulfonic acid (23.7 parts), cyanuric chloride (9.3 parts) and 1-aminobenzene-4-β-sulfatoethylsulfone (14.1 parts) were subjected to condensation in an aqueous medium one after another in a usual manner. Successively, the condensate was allowed to react with 1-aminobenzene-3-β-sulfatoethylsulfone (14.1 parts) at 60° to 70° C. under a weak acid condition. Thereafter, the reaction mixture was salted-out to separate crystals, thereby obtaining an anthraquinone compound of the following formula in the free acid form. ##STR24##
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[Na+].Br[C:40]#[N:41]>O1CCOCC1.O>[NH2:41][C:40]1[O:23][C:22]([C:21]2[C:20]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[CH:19][C:18]([CH2:31][CH3:32])=[C:17]([CH:26]=2)[C:15]([N:12]2[CH2:11][CH2:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)([F:33])[CH2:14][CH2:13]2)=[O:16])=[N:24][N:25]=1
Reactant: N#CBr
Reactant: CCc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide (compound 217.2, 450 mg, 1.00 mmol, 1.00 equiv) in 1,4-dioxane (10 mL). A solution of sodium bicarbonate (252 mg, 3.00 mmol, 2.99 equiv) in water (10 mL) and BrCN (128 mg, 1.21 mmol, 1.20 equiv) were added to the reaction mixture. The resulting solution was stirred for 3 h at room temperature, then quenched with 30 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 400 mg (84%) of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile as a light brown solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].C([O-])(=O)C.[Na+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCN(C4COC4)CC3)nc2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(N4CCN(C5COC5)CC4)nc3)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 197e (200 mg, 0.48 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (364 mg, 0.95 mmol), PdCl2(dppf) (40 mg, 0.049 mmol), K3PO43H2O (250 mg, 0.95 mmol), sodium acetate (80 mg, 0.95 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 197f as a red solid (230 mg, 70%). MS-ESI: [M+H]+ 680
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:26]([F:29])([F:28])[F:27])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][NH:24][CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9].[N:30]#[C:31]Br.FC1C(C(F)(F)F)=C(C2CCN(C(N3C4CN(C#N)CC=4C=N3)=O)CC2)C=CC=1F>>[F:2][C:3]1[C:4]([C:26]([F:27])([F:28])[F:29])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][N:24]([C:31]#[N:30])[CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: N#CBr
Reactant: O=C(c1n[nH]c2c1CNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Agent: Cl
Agent: N#CN1Cc2cnn(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)c2C1
Product: N#CN1Cc2[nH]nc(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)c2C1

Procedure:
Following general procedure GP-J2, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone (38) and cyanogen bromide were converted to -(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carbonitrile as a white solid (23 mg, 79%): No clear melt observed; 1H NMR (500 MHz, DMSO-d6) δ 13.623-13.172 (m, 1H), 7.850-7.664 (m, 1H), 7.664-7.470 (m, 1H), 5.552-3.846 (m, 6H), 3.271-2.652 (m, 3H), 2.042-1.503 (m, 4H); ESI MS m/z 426 [M+H]+.