Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][NH:32][C:33]([NH:35][OH:36])=[NH:34].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:31][NH:32][C:33](=[NH:34])[NH:35][OH:36])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1cc(Cl)sc1Cl)C2
Temperature: 105 °C
Reaction time: 2 h
Yield: 121.7 %

Procedure:
A mixture of 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (250 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (314 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (4 ml) was stirred at 105° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (40 ml), tetrahydrofuran (25 ml) and 0.2 N sodium hydroxide (25 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (15 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (0.8 ml), and the mixture was concentrated under reduced pressure. To the residue was added ethanol (4 ml), and the mixture was stirred at 90° C. (bath temperature) for 3 hours and cooled to give crystals, which were filtered, washed with ethanol and dried to give 7-(2,5-dichlorothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 105) (205 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16](C)[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:23])[CH:3]=1.C1C=CC2N(O)N=[N:30][C:28]=2C=1.C(N(CC)CC)C.CN.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(OCC)(=O)C.O>[CH3:28][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([F:19])[C:13]2[N:14]=[CH:15][NH:16][C:12]=2[CH:11]=1)=[O:22]
Reactant: On1nnc2ccccc21
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid 10c (0.029 g, 0.076 mmol) is dissolved in N, N-dimethylformamide (1.1 mL). HOBT (0.016 g, 0.10 mmol), triethylamine (0.028 mL, 0.20 mmol), methylamine (0.059 mL, 0.12 mmol, 2 M solution in tetrahydrofuran), and EDCl (0.019 g, 0.10 mmol) are added consecutively to the reaction mixture at room temperature. The solution is stirred at room temperature for 16 hours under N2. The reaction mixture is poured into a separatory funnel and diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed successively with aqueous saturated NH4Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water (1×), and brine (1×), dried (MgSO4) and concentrated under reduced pressure. The resulting solid is purified by FCC (eluting with 19:1 methylene chloride:methanol) to yield 0.013 g (42%) of the pure desired product. MS APCI (+) m/z 397, 399 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (broad s, 1H), 8.69 (m, 1H), 8.41 (s, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.30 (dd, 1H), 6.50 (dd, 1H), 2.76 and 2.75 (s and s, 3H total, amide rotamers). 19F NMR (376 MHz, DMSO-d6)−132.69 (s).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)=[O:19].O>[Al].[Ni]>[N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:19])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=CO
Reactant: CCCC(c1ccc(C#N)cc1)n1ccnc1
Agent: [Ni]
Agent: [Al]
Solvent: O
Product: CCCC(c1ccc(C=O)cc1)n1ccnc1

Procedure:
10 g of nitrile of example 4 is refluxed with 10 g of aluminum nickel alloy in 150 ml of formic acid/water (75:25) for 1 hour. It is filtered on kieselguhr, the filtrate is alkalized with solid potassium carbonate, 100 ml of aqueous ammonia is added and extracted with ether. After drying and concentration by evaporation of the ether, it is distilled on a bulb tube; 9.1 g of 4-[1-(1-imidazolyl)butyl]-benzaldehyde is obtained, melting 200° C./0.03 mbar.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29](O)=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:44][C:45]1[CH:46]=[CH:47][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:49][CH:50]=1.CCCCCCC=CCCC>O1CCCC1>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH:54][S:51]([C:48]3[CH:49]=[CH:50][C:45]([CH3:44])=[CH:46][CH:47]=3)(=[O:52])=[O:53])=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)N(CCCCOCC(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CCCC=CCCCCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)COCCCCN(c2cnc(-c3ccccc3)c(-c3ccccc3)n2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a solution of 500 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid obtained in Example 42 in 5 ml of anhydrous tetrahydrofuran, 214 mg of 1,1′-carbonyldiimidazole was added and, after stirring at room temperature for 30 minutes, the mixture was heated at reflux for 30 minutes. After air-cooling to room temperature, 206 mg of p-toluenesulfonamide was added. After stirring for 10 minutes, 0.18 ml of 1,8-diazabicyclo[5.4.0.]undec-7-ene was added dropwise. After stirring at room temperature overnight, almost all of the solvent was evaporated under reduced pressure. The residue was combined with water and then neutralized with 1N hydrochloric acid. The reaction solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 460 mg of the desired compound.
Reaction SMILES: C([O:4][CH:5]=[CH2:6])(=O)C.[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:9]1([C@@H:5]([OH:4])[CH3:6])[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCC
Reactant: C=COC(C)=O
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
(R, S)-1-phenylethanol (0.276 gram, 2 mmol) and vinyl acetate (0.17 gram, 2 mmol) were dissolved in 10 ml of n-hexane dried in advance on Molecular Sieve 4A for one day. To the resulting solution was added 1 gram of PPL (porcine pancrea lipase: Product of Sigma), and the mixture was stirred at 25° C. and 150 r.p.m. to give (S)-1-phenylethanol in an optical purity of 90% with a theoretical yield of 85%.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([C:23]([O:25]C)=[O:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[Li+].[OH-]>CO>[CH3:3][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([C:23]([OH:25])=[O:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:1]
Reactant: COC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Yield: 74.6 %

Procedure:
To a solution of methyl 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-13-carboxylate (1.40 g, 3.95 mmol) in MeOH (25 ml) was added LiOH (2.0 N, 10 ml). The resulting solution was heated to reflux for overnight. The volatiles were removed in vacuo and the residue was adjusted to pH around 6-7 using 1 N HCl. The solid was collected and dried under reduce pressure to give the desired product (1.0 g, 75% yield) as a brown solid. LCMS m/z [M+H]+ 340.2.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29]C)=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(=O)([O-])O.[Na+]>C(#N)C.O>[CH3:26][O:25][C:24]1[C:3](=[O:2])[C:4]([CH3:31])=[C:5]([CH2:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=2)[C:22](=[O:29])[C:23]=1[O:27][CH3:28]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.1 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl) benzoic acid (30 mg, 1.1820 mmol) was dissolved in a mixed solvent of acetonitrile (6 ml) and water (2 ml), then CAN (97 mg, 0.1770 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (10% methanol-methylene chloride) to give the title compound (10 mg, 0.0254 mmol, 36%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][N:2]=1.CO.[CH2:12](Cl)Cl>>[CH3:12][C:3]1[N:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccnnc1
Reactant: ClCCl
Solvent: CO
Product: Cc1nnccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-pyridazinecarboxylic acid (490 mg, 3.9 mmol) in MeOH/DCM (20/10 ml) was added at 0° C. trimethylsilildiazomethane (25.5 mmol). The solution was warm at r.t. and stirred overnight. Volatiles were evaporated in vacuo, the crude dissolved in DCM, washed with NaHCO3 satured and dried over Na2SO4. After filtration and concentration to dryness in vacuo, the crude was purified by column chromatography (DCM:MeOH=98 to 2) to give 400 mg of the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCOc1ccccc1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A mixture of N-(4-phenoxybutyl)phthalimide (7.8 g), hydrazine hydrate (7 ml) and ethanol (150 ml) was stirred for one hour under reflux. Crystalline precipitate was filtered off, then the filtrate was concentrated under reduced pressure to give 4-phenoxybutylamine (4.2 g, 95%) as an oily product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-cyanophenol and methyl bromoacetate in CH3CN was treated with K2CO3 and refluxed for 18 hours. Then the reaction was cooled to room temperature and concentrated. The residue was partitioned between EtOAc and H2O and the organic layer was washed with brine, driend (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, hexanes/EtOAc) gave pure methyl 2-(4-cyanophenoxy)acetate.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:23])[CH3:2].C1(=O)CCCCC1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CCC2=O
Yield: 65.9 %

Procedure:
Reflux dl-13-ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17β-ol (5.5 g) in toluene (200 cc) and cyclohexanone (70 cc) with aluminum isopropoxide (4.0 g) for 2.5 hours. Add water and anhydrous sodium sulfate, filter and isolate the crude product. Triturate with ice cold methanol to obtain dl-13-ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17-one (3.6 g), m.p. 118°-125°, λ max. KBr 5.78 μ, 5.90 μ, 6.0 μ. An analytical sample recrystallized from methanol has m.p. 163°-166°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].O[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: OCCN1CCOCC1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 506 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (2 g, 6.79 mmol) prepared in Preparation Example 2 was dissolved in THF/benzene (270 mL/90 mL) solution, and 2-hydroxyethylmorpholine (5.83 g, 44.45 mmol) and triphenylphosphine (11.66 g, 44.45 mmol) were added thereto and kept at 0° C. Diisopropyl azodicarboxylate (8.99 g, 44.45 mmol) was added dropwise to the mixture, followed by stirring for 2 hrs at room temperature. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 14 g of the titled compound (yield: 93%) as a red solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1)=O)C.[C:23](OCC)(=O)C>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:10]=[CH:9][C:8]([CH:6]([CH3:23])[CH2:5][C:4]([OH:3])=[O:22])=[CH:13][CH:12]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-butenoic acid, obtained by reacting 3-(2',4'-difluoro-4-biphenylyl)-3-oxopropionic acid ethyl ester with triphenylphosphinemethylene and saponifying the reaction product, is dissolved in 25 ml. of ethyl acetate and hydrogenated on 0.1 g. of platinum at 20° and under 1 atmosphere until the absorption of hydrogen has ceased. The mixture is filtered and the filtrate is evaporated to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([N:25]1[N:29]=[C:28]([CH3:30])[O:27][CH2:26]1)=[CH:14][CH:13]=2)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([N:25]1[N:29]=[C:28]([CH3:30])[O:27][CH2:26]1)=[CH:14][CH:13]=2
Reactant: CC1=NN(c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)CO1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1=NN(c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)CO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.7 %

Procedure:
To tert-butyl[2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-3-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.20 g, 0.41 mmol) was added a solution (4 mL) of 4N hydrogen chloride in ethyl acetate and the mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure and to the residue was added diisopropyl ether (5 mL). The precipitated powder was collected by filtration. To this powder was added saturated aqueous sodium hydrogencarbonate (30 mL) and the mixture was extracted twice with a solution (25 mL) of ethyl acetate-tetrahydrofuran (1:1). The organic layers were combined and the mixture was washed with saturated brine (25 mL), dried over anhydrous magnesium sulfate (15 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1, (v/v)) and recrystallized from n-hexane-ethyl acetate (5:1) to give the title compound (0.11 g, 72%) as pale-yellow crystals.
Reaction SMILES: CN1CCN(C)[C:4](=[O:9])[C:3]1=[O:10].[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[C:13]([Mg]Cl)[CH:12]=1>C1COCC1>[CH3:19][C:11]1[CH:16]=[C:15]([C:3]([C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH3:19])[CH:12]=2)=[O:9])=[O:10])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc([Mg]Cl)c1
Reactant: CN1CCN(C)C(=O)C1=O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)C(=O)c2cccc(C)c2)c1
Yield: 35 %

Procedure:
Mueller-Westerhoff9 and co-workers reported a simple, high-yield two-step synthesis of symmetrically substituted α-diones. The first step involves the preparation of 1,4-dimethylpiperazine-2,3-dione (13). Compound 13 was prepared in high yield from the reaction between N,N′-dimethylethylenediamine and diethyl oxalate in anhydrous diethyl ether at room temperature overnight. Second, compound 13 reacts with 2 equivalents of organolithium or Grignard compounds to form symmetrically-substituted α-diones after hydrolysis. 3,3′-Dimethylbenzil was prepared from the reaction between compound 13 and 2 equivalents of m-tolylmagnesium chloride in dry THF, followed by acidic workup in 35% yield (not optimized). Bis[1,2-di(3-methylphenyl)ethane-1,2-dithiolene]nickel (17) was then prepared by Schrauzer and Mayweg procedure as shown in FIG. 8.10
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([OH:25])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:27]1[C:31]2C=CC=CC=2N=N1.CN>ClCCl>[CH3:31][NH:27][C:23](=[O:25])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC2CCCC2)cc1)C(=O)O
Agent: CN
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC2CCCC2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 14 %

Procedure:
To a cold (0°) solution of N-(Tertiarybutoxycarbonyl)-O-cyclopentyl-L-tyrosine (6.89 g, 20 mM) in dichloromethane (40 ml) was added 1-hydroxybenzotriazole (3.32 g, 21 mM) and dicyclohenylcarbodiimide (4.47 g, 21 mM). After 20 minutes at 0° a solution of methylamine (1.34 g, 40 mM) in dichloromethane (20 ml) was added and the reaction mixture was allowed to stir and warm to room temperature overnight. The reaction mixture after filtration and washing with water, dilute (1M) sodium hydroxide, 3N citric acid and water was dried and concentrated in vacuo to an oil. Recrystallisation from ethyl acetate/hexane gave the title compound as white crystals (1 g); m.p. 152°-154°; (Found: C, 66.77; H, 8.47; N, 7.83. C20H30N2O4 requires C, 66.27; H, 8.34; N, 7.73%); δ(CDCl3) 1.40 (9H, s, C(CH3)3); 1.5-2.0 (8H, CH-cyclopentyl); 2.72 (3H, d, J=5 Hz, CONHCH3); 2.95 (2H, m, CH2Tyr); 4.22 (1H, dd, J=7 and 15 Hz,α-CH); 4.72 (1H, br, O--CH (cyclopentyl)); 5.07 (1H, br, CONH); 5.75 (1H, br, CONH); 6.78 (2H, d, J=8 Hz, C6H4); 7.10 (2H, d, J=8 Hz, C6H4).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][C:19]2[N:23]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:12]=1>C1COCC1.C(OCC)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([CH2:18][NH:17][C:13]3[N:14]=[C:15]([O:7][C@@H:4]4[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]4)[CH:16]=[CH:11][N:12]=3)=[C:20]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[N:21]=2)[CH:24]=1
Reactant: CN1CC[C@@H](O)C1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2nccc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-1-methylpyrrolidin-3-ol (66 mg, 0.65 mmol) in THF (3 ml) was added NaH (25 mg, 65% in mineral oil). The mixture was stirred for 30 min and 4-chloro-N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine (50 mg, 0.13 mmol) was added. The mixture was heated from 65 to 95° C. until the reaction was completed. The mixture was diluted with ethyl acetate and the resulting mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated by evaporation. The crude product was purified by silica gel chromatography (methanol/methylene chloride gradient) to obtain the desired product. 1H-NMR (CDCl3, 400 MHz, δ) 8.23 (s, 1H), 7.69 (m, 2H), 7.52 (d, J=9.5 Hz, 1H), 7.12 (m, 3H), 5.97 (s, 1H), 5.36 (s, 1H), 4.96 (d, J=4.7 Hz, 2H), 2.80 (m, 3H), 2.68 (m, 1H), 2.34 (s, 3H), 2.25 (m, 2H), 1.96 (m, 1H) ppm; m/e 453 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21](C)(C)[O:22][SiH2]C(C)(C)C)[CH:15]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][OH:22])[CH:15]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)CC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CO)c1)CC(F)F
Yield: 81.2 %

Procedure:
{2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl}-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (7.50 g, 16.2 mmol) was dissolved in MeOH (323 mL). Aq. 1M NaOH (161 mL) was added, and the mixture was heated to reflux for 1 h. The solvents were partially removed under reduced pressure, and the aq. residue was diluted with water (900 mL). The mixture was extracted with Et2O (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield to crude title compound (4.60 g, 81%) that was used further without purification. LC-MS: tR=1.00 min; ES+: 317.31.