Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:6]=1[NH2:7].[CH3:19]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]([C:3]1[C:2]([CH3:19])=[C:6]([NH2:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:4]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)c(Br)c1N
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(C(C)(C)C)c(C)c1N
Temperature: 155 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
To a solution of 4-bromo-3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate J, 800 mg, 2.60 mmol) in DMF (5 mL) was added trimethylboroxine (0.73 mL, 5.19 mmol), [1,1′-bis(diphenylphosphino)-butane]palladium (II) dichloride (157 mg, 0.26 mmol), and potassium carbonate (1.08 g, 7.79 mmol). The reaction mixture was stirred for 18 h at 155° C. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using hexane/EtOAc (1:9, v/v) to afford the product (243 mg, 38%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 1.24 (s, 9H), 1.97 (s, 3H), 2.03 (s, 3H), 4.48 (s, 2H) 7.14-7.32 (m, 4H). ES-MS m/z 244.2 (MH+); HPLC RT (min) 1.17.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:21]=[CH:20][N:19]=1>CN1C(=O)CCC1.CO>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:22]3[CH:21]=[CH:20][N:19]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:23]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)n(C)c12
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc(C(=O)c2ccnc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12

Procedure:
0.40 g (1.8 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.18 g (0.60 mmol) 6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred overnight in 3 mL NMP at 120° C. The reaction mixture was diluted with MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:36]O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:36])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:23])[F:24])[O:11][N:10]=1
Reactant: CO
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 9 %

Procedure:
To a mixture of 3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.1 mmol) in methanol (1.5 mL) was added thionylchloride (5 μL, 0.1 mmol). The mixture was stirred at room temperature for 60 h and for 5 h at reflux. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product (example B-67) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5](OC)=[O:6].[NH2:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([NH:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:6]
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(C)c1
Reactant: Cc1ncccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccnc2C)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a mixture of methyl 3-methyl-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.20 g, 0.51 mmol) and 3-amino-2-methylpyridine (0.066 g, 0.61 mmol) in anhydrous THF (20 mL), was added lithium bis(trimethylsilyl)amide solution (1.01 mL, 1 M in THF, 1.01 mmol), at about −60° C. The resulting mixture was stirred for about 30 min, during which time the temperature was allowed to rise from about −60° C. to about 0° C., and then quenched by the addition of water (20 mL), while keeping the temperature below 0° C. The resulting mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate) to afford 3-methyl-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.10 g, 0.21 mmol, 42%) as a beige foam: LC-MS (Table 1, Method a) Rt=1.85 min, m/z 471 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.56 (3H, s) 2.72 (3H, s) 2.67-2.75 (1H, m) 2.87 (1H, ddd, J=15.0, 9.3, 2.6 Hz) 3.29 (1H, ddd, J=13.3, 9.3, 2.5 Hz) 3.65 (1H, ddd, J=13.3, 6.2, 2.3 Hz) 3.85 (3H, s) 3.87 (1H, br s) 6.76 (1H, s) 7.08 (1H, ddd, J=7.4, 4.9, 1.1 Hz) 7.20 (1H, dd, J=8.1, 4.7 Hz) 7.35 (1H, t, J=8.0 Hz) 7.55 (1H, dd, J=8.0, 2.0 Hz) 7.60 (1H, td, J=7.8, 1.8 Hz) 7.62 (1H, d, J=1.8 Hz) 7.69 (1H, br s) 7.84 (1H, dt, J=8.0, 1.0 Hz) 8.30 (1H, dd, J=4.8, 1.6 Hz) 8.35 (1H, dd, J=8.1, 1.4 Hz) 8.47 (1H, ddd, J=4.8, 1.7, 0.8 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:18][CH2:19][CH3:20].[Na+].C(Cl)(=O)C.Cl>O1CCCC1>[C:19]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:18])[CH3:20]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CCOC(=O)C(C(C)=O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-phenylmalonate (100 mmol) in anhydrous tetrahydrofuran (300 mL) is added sodium ethoxide (110 mmol). The mixture is stirred at room temperature for 30 min, followed by the addition of a solution of acetyl chloride (110 mmol) in tetrahydrofuran (50 mL). After the addition is complete, the mixture is heated to reflux for 3 hours, cooled to room temperature, neutralized with 2 N HCl, then concentrated in vacuo. The residue is partitioned between H20 and CHCl3, the organic extracts washed with sodium bicarbonate, water, and brine, dried (MgS04), filtered and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)=[O:4].[C:28](Cl)(=O)C>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]([CH3:28])=[CH:27][CH:26]=[CH:25][CH:24]=[CH2:23])=[CH:8][C:9]=1[NH:10][CH:11]([CH3:21])[CH2:12][OH:13])=[O:4]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CO[Si](C)(C)C(C)(C)C
Solvent: CO
Product: C=CC=CC=C(C)c1cc(NC(C)CO)c(C(=O)OC)s1
Yield: 79 %

Procedure:
To a solution of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethylamino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.08 g, 2.69 mmol) in MeOH (10 ml) at 21°, under N2 was added a solution of acetylchloride premixed in MeOH (100 μL/1 mL, 210 μL 2.96 mmol, 1.1 eq). The reaction was followed by tlc. On completion the reaction was stripped-off solvent and the residue purified over silica using progressively 5%, 20%, and then 30% EtOAc/Hexane as eluent to give 3-(2-Hydroxy-1-methyl-ethylamino)-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester as a yellow solid (518 mg, 79%); 1H NMR (300 MHz, CDCl3) 1.25 (d, 6.6 Hz, 3H), 3.52-3.62 (m, 1H), 3.73-3.77 (m, 2H), 3.84 (s, 3H), 6.92 (s, 1H), 7.36-7.42 (m, 3H), 3.62 (d, J=8.3 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[Br:22][C:20]1[CH:21]=[C:16]([O:15][CH:4]([CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[CH2:3][OH:2])[CH:17]=[N:18][CH:19]=1
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)Oc1cncc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC(Cc1c[nH]c2ccccc12)Oc1cncc(Br)c1
Yield: 42 %

Procedure:
To a solution of Example 405A (3.2 g, 8.5 mmol) in THF (20 mL) and ether (30 mL) was slowly added LiAlH4 powder (323 mg, 8.5 mmol) in several portion at rt. While LAH was added a lot of solid material precipitated from the solution and the temperature arises to about 40° C. Water (2 mL) and diluted HCl was added slowly and the mixture was neutralized with NaHCO3 and extracted with ethyl acetate. The organic phase was washed with water and concentrated. The residue was separated by flash chromatography (20-80% EtOAc in hexane) to give the desired product (1.24 g, 42%). MS (DCI) m/z 347, 349 (M+1)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccccc3c2)c1
Yield: 76 %

Procedure:
Under an argon gas atmosphere, 243 g (1.41 mol) of 2-naphthaleneboronic acid, 400 g (1.41 mol) of 3-bromoiodobenzene, 3.27 g (28.2 mmol) of tetrakis(triphenylphosphine)palladium(0), 6.4 L of toluene and 3.2 L of aqueous solution of 2M sodium carbonate were added together, and stirred while being refluxed for 24 hours. After the reaction was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was washed by water and dried with magnesium sulfate, the toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 303 g of 2-(3-bromophenyl)naphthalene was obtained at an yield of 76%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[C:27]#[N:28])[NH:12][CH:13]=[C:14]1[C:19](=[O:20])OC(C)(C)OC1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:24]([C:19](=[O:20])[CH:14]=[CH:13][NH:12]2)=[CH:25][C:26]=1[C:27]#[N:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C#N)c(OCc3ccccc3)c2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: N#Cc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 190 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
5-((3-Benzyloxy-4-cyanoanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6 g, 15.9 mmol) was suspended in DOWTHERM A, (trade mark of Fluka Chemie AG), (100 ml) and heated to 190° C. The mixture was stirred for 1 hour at 190° C. Upon cooling to ambient temperature the product precipitated out. Ether (125 ml) was added and the suspension was stirred for 30 minutes. The product was collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-6-cyano-1,4-dihydroquinolin-4-one (3.5 g) which was used without further purification in the next step.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([CH3:28])[CH:20]=[CH:19][C:18]([NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.[CH:29]([CH2:31][C:32]1([CH2:38][CH2:39][N:40]2[C:44](=[O:45])[C:43]3=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]3[C:41]2=[O:50])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[C:15]1([CH3:28])[CH:16]=[CH:17][C:18]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:29][CH2:31][C:32]3([CH2:38][CH2:39][N:40]4[C:44](=[O:45])[C:43]5=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]5[C:41]4=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:24][CH2:23]2)=[CH:19][CH:20]=1
Reactant: O=CCC1(CCN2C(=O)c3ccccc3C2=O)CCCCC1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(NC2CCN(CCC3(CCN4C(=O)c5ccccc5C4=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.4 %

Procedure:
After adding sodium triacetoxyborohydride (0.82 g, 3.85 mmol) to a solution of 4-(p-toluidino)piperidine (0.73 g, 3.85 mmol), N-[2-[1-(formylmethyl)cyclohexyl]ethyl]phthalimide (0.77 g, 2.57 mmol) and acetic acid (0.30 mL, 5.14 mmol) in 1,2-dichloroethane (10 mL), the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium hydrogencarbonate was then added, and extraction was performed with chloroform-ethanol (10:1). After drying (anhydrous sodium sulfate), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (25 g Merck Art 9385, chloroform:methanol=20:1) to obtain the title compound as a colorless oil (1.32 g).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17]([CH3:19])=[O:18])=[CH:3]1.CO.C(OCC)(=[O:24])C>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17]([CH3:19])(=[O:24])=[O:18])=[CH:3]1
Reactant: Cn1cc(S(C)=O)c(=O)c2ccc(C(F)(F)F)cc21
Reactant: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(C(F)(F)F)cc21

Procedure:
1-methyl-3-methylsulphinyl-7-trifluoromethyl-4-quinolone was oxidised in dichloromethane at 0° to give 1-methyl-3-methylsulphonyl-7-trifluoromethyl-4-quinolone, m.p. 300°-301° (from methanol:ethyl acetate)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[CH2:40]=[C:41]([CH2:44]O)[CH2:42][OH:43].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:40]=[C:41]1[CH2:42][O:43][C:2]2([CH2:7][CH2:6][CH:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]5[NH:32][C:31](=[O:33])[O:30][N:29]=5)=[CH:20][CH:21]=4)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]4[N:37]=[CH:38][N:39]=[C:9]34)[CH2:4][CH2:3]2)[O:1][CH2:44]1
Reactant: C=C(CO)CO
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C1COC2(CCC(n3c(=O)c(Cc4ccc(-c5ccccc5-c5noc(=O)[nH]5)cc4)c(CCC)n4ncnc34)CC2)OC1
Yield: 19 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.20 g), 2-methylidenepropane-1,3-diol (0.067 g), 4-methylbenzenesulfonic acid (0.0072 g) and toluene (20 mL) was heated under reflux for 1.5 hr using a Dean-Stark trap. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.043 g, 19%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[CH:44]=[C:45]([CH3:48])[CH:46]=[CH:47][C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4cc(C)ccc4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-5-methylphenyl)boronic acid gave 264. 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.92-7.82 (m, 2H), 7.44 (br, 2H), 7.29-7.19 (m, 2H), 5.12 (t, J=5.4 Hz, 1H), 3.97-3.88 (m, 2H), 3.71 (s, 3H), 3.53-3.44 (m, 1H), 3.34-3.23 (m, 1H), 3.04 (s, 3H), 2.37 (s, 3H), 1.78-1.50 (m, 4H). LCMS (ES+) m/z 475 (M+1).
Reaction SMILES: [C:1]([NH:11][CH:12]([C:18](=[O:20])[CH3:19])[CH2:13][C:14]([O:16]C)=[O:15])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:19][C:18]1[O:20][C:1]([CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][C:12]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CC(NC(=O)C=Cc1ccccc1)C(C)=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1oc(C=Cc2ccccc2)nc1CC(=O)O

Procedure:
A mixture of methyl 3-cinnamoylamino-4-oxovalerate (2.2 g), phosphorus oxychloride (2.2 ml) and toluene (24 ml) was refluxed with stirring for an hour. The solvent was distilled off and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and ethanol (8 ml) and 2N sodium hydroxide (8 ml) were added to the residue. The mixture was stirred for 30 minutes and adjusted to pH 2 with diluted hydrochloric acid. The resulting crystalline precipitate was collected by filtration to give 5-methyl-2-styryl-4-oxazoleacetic acid; yield 1.50 g (77.3%). Recrystallization from ethanol gave pale brown needles melting at 182°-183° C. The IR and NMR spectra of this product were in good agreement with those of the compound obtained in Example 1.
Reaction SMILES: [CH2:1]([C:4]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[CH:14]([OH:19])[C:15](OC)=[O:16])[CH2:2][CH3:3].[NH2:34][C:35](N)=[O:36].C[O-].[Na+]>>[CH2:1]([C:4]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:14]2[O:19][C:35](=[O:36])[NH:34][C:15]2=[O:16])[CH:20]=[CH:21][CH:22]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(C(O)C(=O)OC)c1
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Na+]
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(C2OC(=O)NC2=O)c1

Procedure:
A solution of methyl 3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)mandelate (194 mg), urea (39 mg) and sodium methoxide (0.90 mL, 0.5 M) was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over sodium sulfate, filtered and evaporated to an oil, which was chromatographed over silica gel with 3% of methanol in methylenechloride to afford the title compound.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:18]C=O)/[CH:6]=[CH:7]/[CH:8]([P:10]([O:15]CC)([O:12]CC)=[O:11])[CH3:9])C.Cl>>[NH2:18][CH:5](/[CH:6]=[CH:7]/[CH:8]([CH3:9])[P:10]([OH:15])([OH:12])=[O:11])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(/C=C/C(C)P(=O)(OCC)OCC)NC=O
Agent: Cl
Product: CC(/C=C/C(N)C(=O)O)P(=O)(O)O

Procedure:
E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester ishydrolysed with 4.35N hydrochloric acid in the manner described in Example 11. E-2-amino-5-methyl-5-phosphono-3-pentenoic acid is isolated in the form of an amorphous white solid mass. 1H-NMR (D2O): 1.05 (dd,3H, CH3); 2.45 (m, 1H, C(5)--H); 4.33 (d, 2H, C(2)--H); 5.5 and 5.9 (2m, 2H, C(3)--H and C(4)--H).
Reaction SMILES: [CH3:1][C:2]1([S:12][CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])([S:12][CH3:13])[C:3]1=[O:11]
Reactant: ClCCOC1CCCCO1
Reactant: CSC1(C)C(=O)Nc2ccccc21
Product: CSC1(C)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:12]>CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1ccc(CBr)cc1

Procedure:
A solution of 4-methoxybenzyl alcohol (6.2 ml, 50 mmol) in dry ether (120 ml) was treated dropwise with phosphorus tribromide (2.07 ml, 22 mmol), refluxed for 1 hour, cooled, washed twice with water, dried and the solvent evaporated. The 4-methoxybenzyl bromide thus produced was added to a mixture of 4-bromo-1,2-dihydro-3,6-pyridazinedione (for a preparation, see B. Kasnar et al, Nucleosides & Nucleotides (1994), 13(1-3), 459-79 or Example 30(a)) (4 g, 21 mmol) and potassium carbonate (8.28 g, 60 mmol) in dry DMF (60 ml) and stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed 3 times with water, dried over magnesium sulfate and evaporated to low volume. Some solid was filtered off and washed with ethyl acetate. The filtrate was evaporated to dryness and the residue chromatographed on silica gel, eluting with 20% ethyl acetate/hexane and then 100% ethyl acetate. This gave the less polar of the 2 desired products (3.233 g), the more polar of the 2 desired products (1.626 g) and a mixture of these (1.351 g). Total yield 6.30 g, 70%.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)(C)C.O>[OH:18][N:17]=[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH2:4]1
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1=C([N+](=O)[O-])CC(=NO)C=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A solution of methyl 4-formyl-2-nitrobenzoate (2.0 g, 9.4 mmol) in isopropanol (50 ml) and water (25 ml) was treated with hydroxylamine hydrochloride (0.7 g) and sodium acetate (0.72 g) and stirred for 2 hours at room temperature. The solvent was then evaporated and the residue was treated with water (25 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 4-hydroxylimino-2-nitrobenzoate (1.8 g). 1H-NMR (400 MHz, CDCl3): 11.90 (1H, s), 8.20 (1H, d), 8.00 (1H, d), 7.89 (1H, d), 3.85 (3H, s) ppm.