Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:39][CH:40]([N-]C(C)C)C.C1COCC1.ICC.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:39][CH3:40])[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1CCN([C@H]2CC[C@@]3(O)[C@H]4Cc5ccc(OCc6ccccc6)c6c5[C@@]3(CCN4CC3CC3)[C@H]2O6)C1=O
Reaction time: 1 h
Yield: 66.6 %

Procedure:
In 5 mL of THF, 248 mg (0.50 mmol) of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1 was dissolved, and 4.1 mL (1.48 mmol) of 0.36N LDA/THF solution was added at 0° C., followed by stirring the mixture for 1 hour. Thereafter, 0.08 mL (0.99 mmol) of iodoethane was added thereto and the resulting mixture was stirred for 3 hours. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 176 mg (yield: 67%) of the captioned compound.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[C:21]2[N:20]=[CH:19][CH:18]=[N:17][C:16]=2[C:15]([C:22]([OH:24])=O)=[CH:14][CH:13]=1.[N+:25]([C:28]1[NH:29][CH:30]=[C:31]([CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[N:32]=1)([O-])=O.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[N:34]1([CH2:33][C:31]2[N:32]=[C:28]([NH:25][C:22]([C:15]3[C:16]4[N:17]=[CH:18][CH:19]=[N:20][C:21]=4[C:12]([C:3]4[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])=[CH:13][CH:14]=3)=[O:24])[NH:29][CH:30]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=[N+]([O-])c1nc(CN2CCCC2)c[nH]1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCCC4)c[nH]3)c3nccnc23)c1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 6 h at 65° C. and using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 94.1). 2-Nitro-4-pyrrolidin-1-ylmethyl-1H-imidazole (Step 19.1) instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. The title compound: ESI-MS: 477.2 [M+H]+; tR=3.28 min (System 1); TLC: Rf=0.11 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>CCCCCC.O.O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:23]([OH:25])=[O:24])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1csc2ccccc12
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1c(C(=O)O)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-tert-Butylbenzothiophene-3-sulfonamide (13.6 g) and 400 ml of anhydrous tetrahydrofuran in admixture were cooled to 0° and 120 ml of butyl lithium in hexane (1.6 molar) was added cautiously, dropwise. After the addition was completed the mixture was stirred at room temperature for 2 hours and carbon dioxide was then passed into the system for two hours while cooling to 15°. Two hundred ml of water was then cautiously added followed by 40 ml of 12 N hydrochloric acid. The solution was then evaporated to half of its original volume, extracted with methylene chloride and the organic phase washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to yield a white solid of m.p. 180° with gas evolution. Nuclear Magnetic Resonance spectroscopy showed the t-butyl absorption at 1.3 δ (singlet) and benzothiophene hydrogen absorption at 7.4-8.0 (multiplet).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]=O)=[CH:4][CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was charged with 6-bromo-2-methylpyridine-3-carbaldehyde (2.50 g, 12.6 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (2.34 g, 12.6 mmol, 1.00 equiv), and dichloromethane (50 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (8.00 g, 37.8 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (22/78) to provide 3.80 g (82% yield) of tert-butyl 4-[(6-bromo-2-methylpyridin-3-yl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 370 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].[Cl-].[Mg+2].[Cl-].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(Cl)Cl.[Cu]Br.O>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][C:18]([C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:19]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: BrCCC1OCCO1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCC2OCCO2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (38 ml) was added dropwise within 15 minutes under argon and while stirring at a maximum 30° C. to a suspension of Rieke magnesium, prepared from 43.5 g of magnesium chloride, in 1300 ml of absolute tetrahydrofuran. The suspension was stirred at room temperature for 30 minutes, cooled to 0° C. and, after the addition of 42.2 g of copper(I) bromide, stirred at 0° C. for 15 minutes. After cooling to -70° C. 50.0 g of 3,4-dimethoxybenzoyl chloride in 200 ml of absolute tetrahydrofuran were added dropwise within 20 minutes. The reaction mixture was stirred at -70° C. for 30 minutes and at room temperature for 2 hours and subsequently hydrolyzed with 1000 ml of saturated ammonium chloride solution while cooling at a maximum 20° C. After the addition of 500 ml of water the mixture was extracted three times with ethyl acetate (1×1000 ml, 2×500 ml). The combined organic extracts were washed with 1000 ml of saturated sodium chloride solution, dried over MgSO4 and freed from solvent. The residue, 69.5 g of dark brown oil, was chromatographed on 1000 g of silica gel with ethyl acetate/hexane (1:1) as the eluent. There were obtained 26.5 g of crude product which were dissolved in a 12-fold amount of n-hexane with the addition of 100 ml of methylene chloride. 50 ml of methylene chloride were distilled off. 22.3 g (34%) of 3-(1,3-dioxolan-2-yl)-3',4'-dimethoxypropiophenone were isolated as colourless crystals which melted at 103°-105° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[Br:1][C:2]1[O:6][C:5]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(Br)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCOCC2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a mixture of 5-bromo-2-furaldehyde (1.76 g) and morpholine (1.00 ml) in 40 mL anhydrous THF at room temperature was added acetic acid (0.60 mL) followed by sodium triacetoxyborohydride (3.28 g). The mixture was stirred at room temperature for 3 h and then poured into a saturated solution of sodium bicarbonate (100 mL). After stirring vigorously for 5 min the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. Purification of the residue by flash chromatography afforded 2.09 g (8.49 mmol, 84% yield) of 4-(5-bromo-2-furylmethyl)morpholine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>CO.ClCCl>[CH2:8]([C:6]1[CH:7]=[C:2]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[N:3]=[CH:4][N:5]=1)[CH3:9]
Reactant: c1nc[nH]n1
Reactant: CCc1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(-n2cncn2)ncn1
Temperature: 120 °C
Yield: 82.2 %

Procedure:
A mixture of 4-chloro-6-ethylpyrimidine (1.42 g, 10 mmol) and 1H-1,2,4-triazole (1.4 g, 20 mmol) was heated to 120° C. with stirring to give a yellow oil, which deposited an orange solid. The mixture was maintained at 120° C. for 0.2 hours, cooled to 70° C. and dissolved in methanol (10 ml). The solution was diluted with dichloromethane (50 ml) and was washed with saturated sodium bicarbonate solution (20 ml). The aqueous phase was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica by elution with ethyl acetate to give the title compound (1.44 g, 82%) as a yellow solid, m.p. 75-76° C., which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([NH2:13])[NH:11][N:12]=1.[Na].[CH:15]([CH2:17][C:18](OCC)=O)=[O:16].Cl>C(O)C.O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[NH:13][CH:18]=[CH:17][C:15](=[O:16])[N:11]2[N:12]=1
Reactant: CCOC(=O)CC=O
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc[nH]c2cc(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine (I-1A-1a; 287 g, 1.48 mol) and ethyl formylacetate sodium salt (517 g, 3.74 mol) in ethanol (12 L) was heated at reflux for 6 hours. Additional ethyl formylacetate sodium salt (100 g, 0.72 mol) was added, and the reaction was heated at reflux for an additional 2 hours. After cooling to room temperature, the reaction was concentrated, in vacuo, to give an amber oil. The residue was redissolved in water (2 L) and then adjusted to pH 8 by dropwise addition of concentrated aqueous HCl. The solid precipitate that formed was isolated by vacuum filtration. This material was suspended in tetrahydrofuran (3 liters) and then stirred overnight. The solid was isolated by vacuum filtration and then dried, in vacuo, to afford I-1A-1b as an off-white solid (356 g, 98%): +APcI MS (M+1) 246.2; 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J=7.5 Hz, 1H), 7.85–7.82 (m, 1H), 7.58–7.53 (m, 1H), 7.46–7.41 (m, 2H), 6.58 (s, 1H), 5.71 (d, J=7.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[N:4][C:3]=1[CH:26]=[C:27]1[C:39](=[O:40])[N:31]2[C:32]3[C:37]([CH:38]=[C:30]2[CH2:29][CH2:28]1)=[CH:36][CH:35]=[CH:34][CH:33]=3.C(O)(=O)C>O>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:26]=[C:27]1[C:39](=[O:40])[N:31]2[C:32]3[C:37]([CH:38]=[C:30]2[CH2:29][CH2:28]1)=[CH:36][CH:35]=[CH:34][CH:33]=3
Reactant: Cc1c(C=C2CCc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1C=C1CCc2cc3ccccc3n2C1=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
A mixture of 8,9-dihydro-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (21.28 g), acetic acid (500 ml), and water (80 ml) was stirred at 80° C. for 1 hour and 10 minutes. After evaporation of the solvent, the residue was diluted with water, neutralized with aqueous sodium bicarbonate solution and 3N aqueous sodium hydroxide solution, and extracted with chloroform to give precipitates. The precipitates were collected, washed with water and chloroform, and dried to give 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (5.8 g). The chloroform layer separated was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to 50 ml. The chloroform solution was diluted with toluene and allowed to stand at room temperature overnight. The crystals were collected and washed with toluene to give a second crop of 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6 (7H)-one (5.2 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nc2ccccn2c1C#Cc1ccccc1
Solvent: ClCCl
Product: ClCc1nc2ccccn2c1C#Cc1ccccc1
Yield: 97.2 %

Procedure:
0.238 g (0.949 mmol) of (3-(phenyl-ethynyl)imidazo[1,2-a]pyridin-2-yl) methanol were dissolved in 5 ml of dichloromethane with magnetic stirring and then 0.346 ml (4.75 mmol) of thionyl chloride were added. The mixture was stirred at r.t. for 2 h before being concentrated in vacuo. The residue was taken up into 20 ml of a mixture consisting of ethyl acetate and of a saturated NaHCO3 aqueous solution (1/1, v/v). After separation, the aqueous phase was extracted with 10 ml of ethyl acetate. The combined organic phases were washed with 10 ml of a saturated NaCl aqueous solution and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 0.246 g (yield=96%) of 2-(chloromethyl)-3-(phenyl ethynyl)imidazo[1,2-a]pyridine were obtained as a brown solid. LC-MS: m/z=267 (MH+); UV purity at 254 nm=98%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[C:14]([NH2:15])=[CH:13][CH:12]=[N:11]1.[Na+].[I-].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[NH:10][N:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccn[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To the solution of 2,4-dichloro-6-methylpyrimidine (3.00 g) and 1H-pyrazol-5-amine (1.31 g) in NMP (30 ml) was added NaI (2.36 g) and DIEA (6.33 ml). And the mixture was heated to 80° C. under stirring. After 1 day, the mixture was cooled to room temperature. The mixture was diluted with EtOAc. The precipitate was collected by filtration, washed with the mixed solvent of hexane and EtOAc and dried in vacuo to give 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine (2.60 g) as a pale pink solid.
Reaction SMILES: C([O:5][C:6](=[O:41])[C:7]([CH3:40])([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:39])[NH:18][C:19]2[CH:20]=[N:21][C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:23][C:24]=2[C:25]([F:28])([F:27])[F:26])=[CH:12][CH:11]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>>[CH3:40][C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:39])[NH:18][C:19]2[CH:20]=[N:21][C:22]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[CH:23][C:24]=2[C:25]([F:26])([F:27])[F:28])=[CH:12][CH:11]=1)([CH3:8])[C:6]([OH:41])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC(=O)Nc2cnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CC(=O)Nc2cnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1)C(=O)O

Procedure:
In analogy to the procedure described in example 124C], 2-methyl-2-(4-{[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid tert-butyl ester was cleaved with trifluoroacetic acid to yield the title compound as light yellow oil.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CC(=O)CC>[OH:10][CH2:9][C:2]1[O:3][CH:4]=[C:5]([O:8][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:6](=[O:7])[CH:1]=1
Reactant: O=c1cc(CO)occ1O
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1cc(CO)occ1OCCN1CCCC1

Procedure:
A mixture of kojic acid (28.4 g, 0.20 mole), 300 mL of 2-butanone, potassium carbonate powder (27.6 g, 0.20 mole), potassium iodide (1.66 g, 0.01 mole), and 1-(2-chloro-ethyl)-pyrrolidine (26.7 g, 0.20 mole) is stirred at a gentle reflux overnight. The reaction mixture is cooled, filtered, washed with acetone and the filtrate evaporated. Water is added and extracted with chloroform (3×100 mL) and ethyl acetate (6×100 mL). The combined organics were dried with sodium sulfate and passed through a pad of magnesol and silica gel eluting with ethyl acetate. The eluate is evaporated in vacuo and crystallized with hexane/ethyl acetate (2/1) to give an off-white solid, 3.05 g, (6%); MS (ES+): m/z 240.3 (M+H).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[O:11]=[C:7]1[NH:6][C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[N:4][C:3]([NH:21][CH2:18][CH2:19][CH3:20])=[C:8]1[C:9]#[N:10]
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: CCCN
Product: CCCNc1nc(Cc2ccsc2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 224 mg (3.80 mmol) of n-propylamine to give 14 mg (13% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]>O1CCOCC1.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)nc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Temperature: 100 °C

Procedure:
To a solution of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione (10 g) in dioxane (200 ml) was added 5% palladium on carbon (5 g). The mixture was heated at 100° C. under 50 kg/cm2 for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to about 70 ml under reduced pressure. The reuulting crystals were collected by filtration and dried at 50° C. under a reduced pressure to give 7.2 g of crude crystals. Recrystallization from acetic acid-water gave crystals of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4thiazolidinedione. Yield: 6.42 g (63.8%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1COCC1.C([Li])CCC.CON(C)[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:44])=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C(=O)c4ccccc4)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol) and THF (5 mL) is added 1.30 M n-Bu-Li (0.50 mL, 0.80 mmol). After 30 minutes N-methoxy-N-methyl-benzamide (0.13 mL, 0.84 mmol) is added, the solution is warmed to ambient temperature, and stirred overnight. The solution is diluted with EtOAc (20 mL), washed with sat. NH4Cl (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.066 g, 0.16 mmol, 21%). 1H NMR (CDCl3), δ 0.89 (t, J=7.4 Hz, 6H), 1.74-1.93 (m, 4H), 2.18 (s, 3H), 2.52 (s, 3H), 2.54 (s, 3H), 3.29-3.38 (m, 1H), 6.71 (s, 1H), 7.49-7.54 (m, 2H), 7.56 (s, 1H), 7.57-7.62 (m, 1H), 7.89-7.94 (m, 2H). LC/MS (m/z): calcd. for C25H27N3OS (M+H)+: 418.2; found: 418.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11](O)[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(Cl)(C)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCc1ccc(CC(O)c2n[nH]c3cc(Cl)ccc23)nc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCc1ccc(C=Cc2n[nH]c3cc(Cl)ccc23)nc1
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a stirred solution of 1-(6-Chloro-1H-indazol-3-yl)-2-(5-ethyl-pyridin-2-yl)-ethanol (232 mg, 0.60 mmol) in CH2Cl2 was added TEA (0.25 mL, 1.81 mmol) and mesyl chloride (0.070 mL, 0.90 mmol). The reaction was stirred for 30 minutes, and then DBU (2 mL) was added. The reaction was refluxed for 18 hours and then quenched with 40 mL of 1 N citric acid. The layers were separated, and the aqueous was extracted with 20 mL CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (12 g silica gel, 50–70% EtOAc/hexanes) yielded the desired compound (135 mg, 71%).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:3]1.[NH2:11][C@@H:12]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:14]>>[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([NH:11][C@@H:12]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)=[O:14])=[O:10])[N:4]=[CH:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1cccc(Oc2ccccc2)c1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Product: O=C(Cc1c[nH]cn1)N[C@@H](COCc1ccccc1)C(=O)Nc1cccc(Oc2ccccc2)c1
Yield: 21 %

Procedure:
Proceeding as in Example 1, but substituting 1H-imidazol-4-ylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(3-phenoxyphenyl)propanamide, gave Compound 243, (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(3-phenoxyphenyl)propanamide (100 mg, 21%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 11.87 (br s, 1H), 10.28 (s, 1H), 8.42-8.41 (d, 1H), 7.54-7.43 (m, 10H), 7.18-7.14 (t, 1H), 7.05-7.03 (d, 2H), 6.95 (s, 1H), 6.75-6.67 (d, 1H), 4.69-4.62 (m, 1H), 4.49 (s, 1H), 3.69-3.60 (m, 2H), 3.51-3.40 (m, 2H). MS (EI) for C27H26N4O4. found 471.0 (MH+).