Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([OH:25])[CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:4][CH2:3]1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([OH:25])[CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3cc([Se]C#Cc4ccc(C(=O)O)c(O)c4)ccc32)cc1
Temperature: 100 °C
Yield: 61 %

Procedure:
1.1 g (2 mmol) of methyl 4-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanylethynyl)-2-hydroxybenzoate (described in Example 5b) are dissolved in 10 ml of tetrahydrofuran, and 0.96 g (24 mmol) of sodium hydroxide is then added. The reaction medium is heated at 100° C. for 14 hours, acidified with 2N hydrochloric acid solution and then extracted with ethyl ether. The residue obtained is purified by chromatography (eluent: 7/3 heptane/ethyl acetate). After recrystallization from a heptane/ethyl ether mixture, a white solid is obtained (0.65 g; yield=61%; m.p.=201° C.).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([C:16]([CH2:27][CH2:28][CH3:29])(C(OCC)=O)[C:17]([O:19]CC)=[O:18])[CH2:14][CH3:15].C(O)C>O>[C:17]([OH:19])(=[O:18])[CH:16]([CH2:27][CH2:28][CH3:29])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(CCC)(C(=O)OCC)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCCC(CCC)C(=O)O
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
A mixture of 70 g of p-toluenesulfonic acid monohydrate, 140 g of diethyl dipropylmalonate and 9 ml of water was heated to reflux in a flask equipped with a distillation column packed with Raschig rings. Ethanol was distilled as it formed and the pot temperature was maintained at 120°-155° C. by periodic addition of water to the pot. After 5 hours, 25 ml of water had been added and the evolution of ethanol had nearly stopped. The mixture was maintained at 140° C. for 18 hours and then was cooled and treated with 100 ml of water. The layers were separated to afford 72.2 g (87.8% yield) of valproic acid as a light brown liquid. The water layer was washed with 50 ml of toluene and the toluene was combined with the crude valproic acid layer. Vacuum distillation afforded a colorless valproic acid fraction (72 g, 87% yield) boiling at 132° C./28" Hg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>O1CCOCC1.CO>[ClH:37].[CH:32]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:36]=[CH:35][C:17]=43)[CH:21]=2)=[N:30][C:29]([CH3:31])=[N:28]1)([CH3:34])[CH3:33]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
To a solution of 4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (569 mg, 1.16 mmol) in dioxane (15 mL) and methanol (5 mL) was added 4M HCl in dioxane (15 mL) and the reaction mixture stirred for 20 h at RT before being concentrated in vacuo. The resultant residue was triturated in a mixture of diethyl ether and methanol to give 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene Hydrochloride as a tan solid (212 mg, 43%). LCMS: RT=2.34/2.66 min, M+H+=393.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=[O:7])[C:5]2[C:8]([CH3:17])=[C:9]([CH3:16])[C:10]([NH:13][CH:14]=[O:15])=[C:11]([CH3:12])[C:4]=2[O:3]1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1>[CH2:19]([C:6]1([OH:7])[C:5]2[C:8]([CH3:17])=[C:9]([CH3:16])[C:10]([NH:13][CH:14]=[O:15])=[C:11]([CH3:12])[C:4]=2[O:3][C:2]1([CH3:18])[CH3:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(C)c2c(c(C)c1NC=O)OC(C)(C)C2=O
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC=O)OC(C)(C)C2(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamide obtained in Reference Example 73 (600 mg, 2.43 mmol) in THF (5 mL) was added dropwise to a solution of benzylmagnesium chloride (a 2.0 M THF solution, 10.0 mL, 20.0 mmol) in THF (20 mL) under argon atmosphere, and the mixture was stirred at room temperature for 2 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain (3-benzyl-3-hydroxy-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)formamide. To a mixture of said compound with trifluoroacetic acid (5 mL) was added triethylsilane (0.5 mL, 3.2 mmol) with ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and to the residue was added a saturated sodium hydrogen carbonate solution to alkalify the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a solution of the obtained residue in methanol (20 mL) was added concentrated hydrochloric acid (10 ml), and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the residue was neutralized with a 12 N aqueous sodium hydroxide solution. After extracting with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 440 mg (yield 62%) of the title compound. Melting point: 75-76° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[O:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1>>[O:9]1[CH:13]=[CH:12][C:11]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)=[CH:10]1
Reactant: OB(O)c1ccoc1
Reactant: O=C1C=C(Br)CCC1
Product: O=C1C=C(c2ccoc2)CCC1
Yield: 16 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and furan-3-boronic acid according to the general procedure described for the Suzuki coupling. Purification by silica gel column chromatography using gradient elution (0 to 30% ether/hexanes) yielded the product (13 mg, 16%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.70 (s, 1H), 7.44 (t, J=1.9 Hz, 1H), 6.59 (t, J=1.1 Hz, 1H), 6.24 (s, 1H), 2.63 (td, J=5.7, 1.1 Hz, 2H), 2.46 (t, J=6.3 Hz, 2H), 2.11 (quintet, J=6.3 Hz, 2H). 13C (75 MHz, CDCl3): 200.1, 152.0, 144.6, 142.4, 126.0, 123.3, 107.6, 37.6, 27.5, 22.7. HRMS (LCT Electrospray): mass calcd for (C10H10O2+Na) m/z 185.0578; measured [M+Na]+: m/z 185.0574.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[C:11]([O:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=2[CH3:35])[N:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH:23]([C:12]1[C:13](=[O:15])[NH:14][C:9](=[O:8])[NH:10][C:11]=1[O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[CH3:35])([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: Cc1cc(C)c(C)c(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C)c(C)c(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 59 %

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-6-(2,3,5-trimethyl-phenoxy)-pyrimidine was dissolved in 6 mL ethyl acetate and 6 mL ethanol mixture. 10% Pd/C (52 mg) was added to the mixture. Then hydrogen balloon was applied. The reaction was stirred at room temperature for 40 minutes. The reaction crude was filtered through celite. The filtrate was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) followed by reverse phase HPLC (MeCN/water) to give white solid (94 mg, 59%). LC-MS shows 289.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.6 (br, 1H), 8.9 (br, 1H), 6.88 (s, 1H), 6.58 (s, 1H), 3.12 (m, 1H), 2.18 (s, 6H), 2.12 (s, 3H), 1.22 (d, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=3)[CH3:18])[C:13]([CH3:33])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:19][NH:20][C:21](=[O:32])[C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)[CH3:18])[C:13]([CH3:33])=[N:12]2)=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=C(C)NNC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 64 %

Procedure:
To 23.2 mg (0.05 mmol) of the 4-methoxycarbonylbenzoic N′-(1-(1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide synthesized in Synthetic Example 4 in 2.0 ml of methanol, 255 μl (0.255 mmol) of 1M aqueous sodium hydroxide was added at room temperature, and the mixture was heated at from 60° C. to 80° C. for 3.5 hours. After it was cooled to room temperature, 255 μl of 1M hydrochloric acid was added, and the precipitated solid was collected by filtration to obtain 13.9 mg of the desired product as a pale brown solid (yield 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.2 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (636 mg, 1.68 mmole), trimethylsilylacetylene (309 μl, 2.19 mmole), bis(triphenylphosphine)palladium chloride (35 mg, 0.05 mmole), copper(I) iodide (19 mg, 0.10 mmole) and triethylamine (352 μl, 2.52 mmole) in tetrahydrofuran (3.4 ml) was stirred at room temperature for 3.5 h before it was partitioned between ethyl acetate and water, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a yellow solid (448 mg). MS: (+) m/z 397.28 (M+1), MS: (−) m/z 395.18 (M−1).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:19]O>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([O:16][CH3:19])=[O:15])=[CH:17][CH:18]=1)([O-:7])=[O:6]
Reactant: CO
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Thionyl chloride (2.3 ml) was added dropwise under ice cooling to a solution of 5.0 g (25 mmol) of 4-nitrophenoxyacetic acid in 250 ml of methanol, followed by stirring at room temperature for 1 hour. After the solvent was distilled out under reduced pressure, the residue was dissolved in 50 ml of methylene chloride, followed by neutralization with an aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over sodium sulfate. The solvent was thereafter distilled out under reduced pressure, whereby 5.2 g of pale yellow powder were obtained (yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:33][C:34]([C:37](Cl)=[O:38])([CH3:36])[CH3:35])(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:37](=[O:38])[C:34]([OH:33])([CH3:36])[CH3:35])[CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2C(=O)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 633 (200 mg, 0.48 mmol), 1-chlorocarbonyl-1-methylethyl acetate (104.3 μL, 0.72 mmol), triethylamine (133 μL, 0.96 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.5 mL) and MeOH (2.0 mL) was added and stirred for 20 min to give the title compound. The compound precipitated out of solution. The precipitate was filtered and washed with water and diethyl ether to obtain a white solid (240 mg, 99%). 1H NMR (400 MHz, (DMSO) δ 8.0 (d, J=8.3, 1H), 7.6 (q, J=8.6 and 6.9 Hz, 1H), 7.3 (td, J=2.5 and 7.8 Hz, 1H), 7.1 (td, J=1.75 and 6.7 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.58 (s, 1H), 5.25 (s, 2H), 4.3 (t, J=8.3 Hz, 2H), 3.42 (t, J=5.4 Hz, 1H), 3.35 (t, J=5.2 Hz, 1H), 3.0 (t, J=8.2 Hz, 2H), 2.3 (s, 3H), 1.3 (s, 6H) ppm. ES-HRMS m/z 503.1561 (M+H calcd for C26H26ClF2N2O4 requires 503.1544).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:9][CH2:8][CH2:7][CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: NCCCn1ccnc1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCn5ccnc5)n4)cc3)cc12

Procedure:
Using 3-imidazol-1-yl-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]O)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(CO)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (200 mg, 0.839 mmol) produced in Example 1 (1C) and 3-nitrobenzyl alcohol (200 mg, 0.926 mmol) were dissolved in acetone (4 mL), and potassium carbonate (136 mg, 0.984 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred at room temperature for 12 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:15][CH2:16]4)=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:22])[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 467.4 [(M+H)+]; mp 235-238° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[N:6][C:5]=1[CH3:15])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:22]1([CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24][CH2:23]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:25][CH:22]3[CH2:24][CH2:23]3)[C:10]2=[O:14])=[N:6][C:5]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1COCCO1
Product: CC(=O)c1sc(N2CCN(CCC3CC3)C2=O)nc1C
Yield: 37 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one (4.50 g, 20.00 mmol), tetrabutylammonium iodide (0.10 g) and potassium carbonate (4.00 g, 28.92 mmol) in 1,4-dioxane (100 mL) was added 2-cyclopropylethyl-4-methylbenzenesulfonate (6.00 g, 24.96 mmol). The reaction mixture was heated to reflux for 37 h. The solvent was removed in vacuo. The residue was dissolved in water (50 mL) and extracted with ethyl acetate. The organic solution washed with water and brine and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to afford 1-(5-acetyl-4-methylthiazol-2-yl)-3-(2-cyclopropylethyl)imidazolidin-2-one in 37% yield (2.20 g): mp 82-83° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 4.12-4.06 (m, 2H), 3.63-3.57 (m, 2H), 3.40 (t, J=7.2 Hz, 2H), 2.60 (s, 3H), 2.44 (s, 3H), 1.51-1.44 (m, 2H), 0.71-0.62 (m, 1H), 0.49-0.43 (m, 2H), 0.09-0.04 (m, 2H); MS (ES+) m/z 294.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][S:13][C:7]=2[CH:6]=1)=[O:4].[BH4-].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[CH:9]([OH:14])[CH2:10][CH2:11][CH2:12][S:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)SCCCC2=O
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)c1ccc2c(c1)SCCCC2O
Yield: 98 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 1 using 5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid methyl ester (3.30 g) and sodium borohydride (529 mg), the objective 5-hydroxy-2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid methyl ester (3.26 g) was obtained a pale yellow oil.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.I[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:40]([O:47][C:48]1[CH:53]=[C:52](I)[CH:51]=[CH:50][C:49]=1[N:55]1[S:59](=[O:61])(=[O:60])[N:58]([CH2:62][CH2:63][Si:64]([CH3:67])([CH3:66])[CH3:65])[C:57](=[O:68])[CH2:56]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:11]([C:52]1[CH:51]=[CH:50][C:49]([N:55]2[S:59](=[O:60])(=[O:61])[N:58]([CH2:62][CH2:63][Si:64]([CH3:66])([CH3:67])[CH3:65])[C:57](=[O:68])[CH2:56]2)=[C:48]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:53]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ICc1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (7.2 g) is placed in a 250 mL round bottom flask, placed under vacuum and heated with a heat gun for 5-8 min. The hot solid is allowed to cool slowly to ambient temperature. DMF (50 mL) is added, followed by 1,2-dibromoethane (0.8 mL). The mixture is placed under an atmosphere of N2 and heated again until effervescence occurs and the reaction maintains itself. The mixture is cooled to ambient temperature and TMSCl (0.8 mL) is added and stirred for 30 min. Iodomethylbenzene (6.2 g, 28 mmol) is added and the mixture stirred for 30 min. at ambient temperature. The reaction is monitored by TLC until the starting material is converted to the Znl, at which point Pd2 dba3 (0.8 g, 0.874 mmol) and P(o-tolyl)3 (1.0 g, 3.28 mmol) are added. A solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (10.0 g, 18.3 mmol) in DMF is added slowly dropwise. The mixture is stirred at ambient temperature overnight. The reaction is diluted with EtOAc, filtered through Celite and washed with EtOAc. The organic mixture is washed with 100 mL of 1N HCl, 150 mL of saturated sodium chloride and dried over MgSO4. The solution is then filtered through a plug of silica gel and concentrated to afford an orange oil. The oil is triturated with 4:1 hexane/ether. The crude material is chromatographed eluting with 4:1 hexane/EtOAc. The pure fractions are concentrated to an orange oil and hexane is added. The solution is filtered and washed with hexane to afford 5-(4-benzyl-2-benzyloxyphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Br:17])[C:15]=1[OH:16])[C:11]#[N:12].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:16][C:15]1[C:14]([Br:17])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[Br:7])=[O:4]
Reactant: C=C(F)C(=O)Cl
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1c(Br)cc(C#N)cc1Br
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
10 g (0.092 mol) α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 5 minutes, to a solution of 24.8 g (0.09 mol) of 3,5-dibromo-4-hydroxybenzonitrile and 9.1 g (0.09 mol) of triethylamine in 200 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-heptane. 17.5 g (55% of theory) of 2,6-dibromo-4-cyanophenyl α-fluoroacrylate were obtained, melting point 135° to 138° C.